Neuroactive steroids and compositions thereof

ABSTRACT

Provided herein is a compound of Formula (I): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein R 1a , R 1b , R 2a , R 2b , R 3 , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7a , R 11a , R 11b , R 12a , R 12b , R 16a , R 16b , R 19 , R 11a , R 22 , R X , R Y  and n are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I) and methods of using the compounds, e.g., in the treatment of CNS-related disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 62/855,435, filed on May 31, 2019, the entire content ofwhich is incorporated by reference herein.

BACKGROUND OF THE INVENTION

Brain excitability is defined as the level of arousal of an animal, acontinuum that ranges from coma to convulsions, and is regulated byvarious neurotransmitters. In general, neurotransmitters are responsiblefor regulating the conductance of ions across neuronal membranes. Atrest, the neuronal membrane possesses a potential (or membrane voltage)of approximately −70 mV, the cell interior being negative with respectto the cell exterior. The potential (voltage) is the result of ion (K⁺,Na⁺, Cl⁻, organic anions) balance across the neuronal semipermeablemembrane. Neurotransmitters are stored in presynaptic vesicles and arereleased under the influence of neuronal action potentials. Whenreleased into the synaptic cleft, an excitatory chemical transmittersuch as acetylcholine will cause membrane depolarization (change ofpotential occurs from −70 mV to −50 mV). This effect is mediated bypostsynaptic nicotinic receptors which are stimulated by acetylcholineto increase membrane permeability to Na⁺ ions. The reduced membranepotential stimulates neuronal excitability in the form of a postsynapticaction potential.

In the case of the GABA receptor complex (GRC), the effect on brainexcitability is mediated by γ-aminobutyric acid (GABA), aneurotransmitter. GABA has a profound influence on overall brainexcitability because up to 40% of the neurons in the brain utilize GABAas a neurotransmitter. GABA regulates the excitability of individualneurons by regulating the conductance of chloride ions across theneuronal membrane. GABA interacts with its recognition site on the GRCto facilitate the flow of chloride ions down an electrochemical gradientof the GRC into the cell. An intracellular increase in the levels ofthis anion causes hyperpolarization of the transmembrane potential,rendering the neuron less susceptible to excitatory inputs, i.e.,reduced neuron excitability. In other words, the higher the chloride ionconcentration in the neuron, the lower the brain excitability and levelof arousal.

It is well-documented that the GRC is responsible for the mediation ofanxiety, seizure activity, and sedation. Thus, GABA and drugs that actlike GABA or facilitate the effects of GABA (e.g., the therapeuticallyuseful barbiturates and benzodiazepines (BZs), such as Valium®) producetheir therapeutically useful effects by interacting with specificregulatory sites on the GRC. Accumulated evidence has now indicated thatin addition to the benzodiazepine and barbiturate binding site, the GRCcontains a distinct site for neuroactive steroids. See, e.g., Lan, N. C.et al., Neurochem. Res. (1991) 16:347-356.

Neuroactive steroids occur endogenously. The most potent endogenousneuroactive steroids are 3α-hydroxy-5-reduced pregnan-20-one and3α-21-dihydroxy-5-reduced pregnan-20-one, metabolites of hormonalsteroids progesterone and deoxycorticosterone, respectively. The abilityof these steroid metabolites to alter brain excitability was recognizedin 1986 (Majewska, M. D. et al., Science 232:1004-1007 (1986); Harrison,N. L. et al., J Pharmacol. Exp. Ther. 241:346-353 (1987)).

New and improved compounds are needed that act as modulating agents forbrain excitability, as well as agents for the prevention and treatmentof CNS-related diseases. The compounds, compositions, and methodsdescribed herein are directed toward this end.

SUMMARY OF THE INVENTION

Provided herein are compounds designed, for example, to act as GABAmodulators. In some embodiments, such compounds are envisioned to beuseful as therapeutic agents for treating a CNS-related disorder.

In an aspect, provided herein is a compound of Formula (I):

or a pharmaceutically acceptable salt thereof;wherein:

-   -   represents a single or double bond, provided if a double bond is        present, then one of R^(6a) or R^(6b) is absent and R⁵ is        absent;    -   R^(X) is selected from the group consisting of halo, —CN, —OH,        —OR^(Q1), and substituted or unsubstituted alkyl, wherein R^(Q1)        is substituted or unsubstituted alkyl;    -   R^(Y) is halo or substituted or unsubstituted alkyl; or    -   R^(Y) and R^(X) may join together with the intervening atoms to        form a substituted or unsubstituted carbocyclyl or a substituted        or unsubstituted heterocyclyl;    -   R³ is selected from the group consisting of substituted or        unsubstituted alkyl, substituted or unsubstituted alkenyl,        substituted or unsubstituted alkynyl, substituted or        unsubstituted carbocyclyl, substituted or unsubstituted        heterocyclyl, substituted or unsubstituted aryl, and substituted        or unsubstituted heteroaryl;    -   R⁵ is hydrogen or methyl;    -   each instance of R²² is independently selected from the group        consisting of halogen, —NO₂, —CN, —OR^(GA), —N(R^(GA))₂,        —C(═O)R^(GA), —C(═O)OR^(GA), —OC(═O)R^(GA), —OC(═O)OR^(GA),        —C(═O)N(R^(GA))₂, —N(R^(GA))C(═O)R^(GA), —OC(═O)N(R^(GA))₂,        —N(R^(GA))C(═O)OR^(GA), —N(R^(GA))C(═O)N(R^(GA))₂, —SR^(GA),        —S(═O) R^(GA), —S(═O)₂R^(GA), —S(═O)₂OR^(GA), —OS(═O)₂R^(GA),        —S(═O)₂N(R^(GA))₂, —N(R^(GA))S(═O)₂R^(GA), substituted or        unsubstituted alkyl, substituted or unsubstituted alkenyl,        substituted or unsubstituted alkynyl, substituted or        unsubstituted carbocylyl, substituted or unsubstituted        heterocyclyl, substituted or unsubstituted aryl, and substituted        or unsubstituted heteroaryl, wherein each instance of R^(GA) is        independently selected from the group consisting of hydrogen,        substituted or unsubstituted C₁₋₆ alkyl, substituted or        unsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆        alkynyl, substituted or unsubstituted C₃₋₆ carbocylyl,        substituted or unsubstituted 3- to 6-membered heterocyclyl,        substituted or unsubstituted aryl, substituted or unsubstituted        heteroaryl, an oxygen protecting group when attached to oxygen,        and a nitrogen protecting group when attached to nitrogen, or        two R^(GA) groups are taken with the intervening atoms to form a        substituted or unsubstituted heterocyclyl or heteroaryl ring;    -   each of R^(1a), R^(1b), R^(2a), R^(2b), R^(4a), R^(4b), R^(7a),        R^(7b), R^(11b), R^(12a), and R^(12b) is independently selected        from the group consisting of hydrogen, halogen, cyano, —NO₂,        substituted or unsubstituted alkyl, substituted or unsubstituted        alkenyl, substituted or unsubstituted alkynyl, substituted or        unsubstituted carbocyclyl, substituted or unsubstituted        heterocyclyl, substituted or unsubstituted aryl, substituted or        unsubstituted heteroaryl, —OR^(A1), —N(R^(A1))₂, —SR^(A1),        —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1), —C(═O)N(R^(A1))₂,        —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)N(R^(A1))₂,        —OC(═O)SR^(A1), —OS(═O)₂R^(A1), —OS(═O)₂OR^(A1),        —OS(═O)₂N(R^(A1))₂, —N(R^(A1))C(═O)R^(A1),        —N(R^(A1))C(═NR^(A1))R^(A1), —N(R^(A1))C(═O)OR^(A1),        —N(R^(A1))C(═O)N(R^(A1))₂, —N(R^(A1))C(═NR^(A1)) N(R^(A1))₂,        —N(R^(A1))S(═O)₂R^(A1), —N(R^(A1))S(═O)₂OR^(A1),        —N(R^(A1))S(═O)₂N(R^(A1))₂, —SC(═O)R^(A1), —SC(═O)OR^(A1),        —SC(═O)SR^(A1), —SC(═O)N(R^(A1))₂, —S(═O)₂R^(A1),        —S(═O)₂OR^(A1), or —S(═O)₂N(R^(A1))₂, wherein each instance of        R^(A1) is independently selected from the group consisting of        hydrogen, substituted or unsubstituted C₁₋₆alkyl, substituted or        unsubstituted C₂₋₆alkenyl, substituted or unsubstituted C₂₋₆        alkynyl, substituted or unsubstituted C₃₋₆carbocyclyl, or        substituted or unsubstituted 3- to 6-membered heterocyclyl,        substituted or unsubstituted aryl, substituted or unsubstituted        heteroaryl, an oxygen protecting group when attached to oxygen,        a nitrogen protecting group when attached to nitrogen, and a        sulfur protecting group when attached to sulfur, or two R^(A1)        groups are taken with the intervening atoms to form a        substituted or unsubstituted heterocyclic ring;    -   each of R^(6a) and R^(6b) is independently selected from the        group consisting of hydrogen, halogen, cyano, —NO₂, —OH,        substituted or unsubstituted alkyl, substituted or unsubstituted        alkenyl, and substituted or unsubstituted alkynyl; or R^(6a) and        R^(6b) are joined to form an oxo (═O) group;    -   each of R^(15a), R^(15b), R^(16a), and R^(16b) is independently        selected from the group consisting of hydrogen, halogen, —CN,        —NO₂, substituted or unsubstituted alkyl, substituted or        unsubstituted alkenyl, substituted or unsubstituted alkynyl,        substituted or unsubstituted carbocyclyl, substituted or        unsubstituted heterocyclyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl, —OR^(C3), —N(R^(C3))₂,        —SR^(C3), —C(═O)R^(C3), —C(═O)OR^(C3), —C(═O)SR^(C3),        —C(═O)N(R^(C3))₂, —OC(═O)R^(C3), —OC(═O)OR^(C3),        —OC(═O)N(R^(C3))₂, —OC(═O)SR^(C3), —OS(═O)₂R^(C3),        —OS(═O)₂OR^(C3), —OS(═O)₂N(R^(C3))₂, —N(R^(C3))C(═O)R^(C3),        —N(R^(C3))C(═NR^(C3))R^(C3), —N(R^(C3))C(═O)OR^(C3),        —N(R^(C3))C(═O)N(R^(C3))₂, —N(R^(C3))C(═NR^(C3)) N(R^(C3))₂,        —N(R^(C3))S(═O)₂R^(C3), —N(R^(C3))S(═O)₂OR^(C3),        —N(R^(C3))S(═O)₂N(R^(C3))₂, —SC(═O)R^(C3), —SC(═O)OR^(C3),        —SC(═O)SR^(C3), —SC(═O)N(R^(C3))₂, —S(═O)₂R^(C3),        —S(═O)₂OR^(C3), or —S(═O)₂N(R^(C3))₂, wherein each instance of        R^(C3) is independently selected from the group consisting of        hydrogen, substituted or unsubstituted C₁₋₆alkyl, substituted or        unsubstituted C₂₋₆alkenyl, substituted or unsubstituted        C₂₋₆alkynyl, substituted or unsubstituted aryl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted        carbocyclyl, or substituted or unsubstituted heterocyclyl, an        oxygen protecting group when attached to oxygen, a nitrogen        protecting group when attached to nitrogen, and a sulfur        protecting group when attached to sulfur, or two R^(C3) groups        are taken with the intervening atoms to form a substituted or        unsubstituted heterocyclic ring;    -   R¹⁹ is hydrogen or substituted or unsubstituted alkyl; and        n is selected from the group consisting of 0, 1, 2, and 3.

In some embodiments, the compound is a compound of Formula I-a:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined above.

In some embodiments, the compound is a compound of Formula I-b1:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined above.

In some embodiments, the compound is a compound of Formula I-c3 orFormula I-c4:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined above.

In some embodiments, the compound is a compound of Formula I-d3 orFormula I-d4:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined above.

In some embodiments, the compound is a compound of Formula I-e5, FormulaI-e6, Formula I-e7, or Formula I-e8:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined above.

In a certain embodiment, the compound is a compound of Formula I-Ib1:

or a pharmaceutically acceptable salt thereof,

-   -   wherein R²² is CN;    -   n is 1;    -   R¹⁹ is selected from the group consisting of hydrogen, ethyl,        and methyl;    -   R^(15a) and R^(15b) is independently selected from the group        consisting of hydrogen, methyl, and cyclopropyl;    -   R^(2a) and R^(2b) is each independently selected from the group        consisting of hydrogen, methyl, ethyl, methoxymethyl, and        methoxy;    -   R³ is selected from the group consisting of unsubstituted C₁₋₃        alkyl, —CH₂OCH₃, and —CH₂OCH₂CH₃;    -   and R^(X) and R^(Y) are as defined herein.

In one embodiment, the compound is a compound of Formula I-Ic1 orFormula I-Ic2:

or a pharmaceutically acceptable salt thereof,

-   -   wherein R²² is CN;    -   n is 1;    -   R¹⁹ is selected from the group consisting of hydrogen, ethyl,        and methyl;    -   R^(15a) and R^(15b) is independently selected from the group        consisting of hydrogen, methyl, and cyclopropyl;    -   R^(2a) and R^(2b) is each independently selected from the group        consisting of hydrogen, methyl, ethyl, methoxymethyl, and        methoxy;    -   R³ is selected from the group consisting of unsubstituted C₁₋₃        alkyl, —CH₂OCH₃, and —CH₂OCH₂CH₃; and    -   R^(X) and R^(Y) are as defined herein.

In one embodiment, the compound is a compound of Formula I-Id1 orFormula I-Id2:

or a pharmaceutically acceptable salt thereof,

-   -   wherein R²² is CN;    -   R¹⁹ is selected from the group consisting of hydrogen, ethyl,        and methyl;    -   R^(15a) and R^(15b) is independently selected from the group        consisting of hydrogen, methyl, and cyclopropyl;    -   R^(2a) and R^(2b) is each independently selected from the group        consisting of hydrogen, methyl, ethyl, methoxymethyl, and        methoxy;    -   R³ is selected from the group consisting of unsubstituted C₁₋₃        alkyl, —CH₂OCH₃, and —CH₂OCH₂CH₃; and    -   R^(X) and R^(Y) are as defined herein.

In one embodiment, the compound is a compound of Formula I-Ie1, FormulaI-Ie2, Formula I-Ie3, or Formula I-Ie4:

or a pharmaceutically acceptable salt thereof,

-   -   wherein R²² is CN;    -   R¹⁹ is selected from the group consisting of hydrogen, ethyl,        and methyl;    -   R^(15a) and R^(15b) is independently selected from the group        consisting of hydrogen, methyl, and cyclopropyl;    -   R^(2a) and R^(2b) is each independently selected from the group        consisting of hydrogen, methyl, ethyl, methoxymethyl, and        methoxy;    -   R³ is selected from the group consisting of unsubstituted C₁₋₃        alkyl, —CH₂OCH₃, and —CH₂OCH₂CH₃; and    -   R^(X) and R^(Y) are as defined herein.

In one aspect, provided herein is a pharmaceutically acceptable salt ofa compound described herein (e.g., a compound of Formula (I)).

In one aspect, provided herein is a pharmaceutical compositioncomprising a compound described herein (e.g., a compound of Formula (I))or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient. In certain embodiments, the compound of thepresent invention is provided in an effective amount in thepharmaceutical composition. In certain embodiments, the compound of thepresent invention is provided in a therapeutically effective amount.

In some embodiments, a method of treating a CNS-related disorder in asubject in need thereof, comprises administering to the subject aneffective amount of a compound described herein (e.g., a compound ofFormula (I)) or a pharmaceutically acceptable salt thereof. In someembodiments, the CNS-related disorder is a sleep disorder, a mooddisorder, a schizophrenia spectrum disorder, a convulsive disorder, adisorder of memory and/or cognition, a movement disorder, a personalitydisorder, autism spectrum disorder, pain, traumatic brain injury, avascular disease, a substance abuse disorder and/or withdrawal syndrome,tinnitus, or status epilepticus. In some embodiments, the CNS-relateddisorder is depression. In some embodiments, the CNS-related disorder ispostpartum depression. In some embodiments, the CNS-related disorder ismajor depressive disorder. In some embodiments, the major depressivedisorder is moderate major depressive disorder. In some embodiments, themajor depressive disorder is severe major depressive disorder.

In some embodiments, the compound is selected from the group consistingof the compounds identified in Table 1 herein.

Compounds of the present invention as described herein, act, in certainembodiments, as GABA modulators, e.g., effecting the GABA_(A) receptorin either a positive or negative manner. As modulators of theexcitability of the central nervous system (CNS), as mediated by theirability to modulate GABA_(A) receptor, such compounds are expected tohave CNS-activity.

Thus, in another aspect, provided are methods of treating a CNS-relateddisorder in a subject in need thereof, comprising administering to thesubject an effective amount of a compound of the present invention. Incertain embodiments, CNS-related disorder is a sleep disorder, a mooddisorder, a schizophrenia spectrum disorder, a convulsive disorder, adisorder of memory and/or cognition, a movement disorder, a personalitydisorder, autism spectrum disorder, pain, traumatic brain injury, avascular disease, a substance abuse disorder and/or withdrawal syndrome,tinnitus, or status epilepticus. In certain embodiments, the CNS-relateddisorder is depression. In certain embodiments, the CNS-related disorderis postpartum depression. In certain embodiments, the CNS-relateddisorder is major depressive disorder. In certain embodiments, the majordepressive disorder is moderate major depressive disorder. In certainembodiments, the major depressive disorder is severe major depressivedisorder. In certain embodiments, the compound is administered orally,subcutaneously, intravenously, or intramuscularly. In certainembodiments, the compound is administered orally. In certainembodiments, the compound is administered chronically. In certainembodiments, the compound is administered continuously, e.g., bycontinuous intravenous infusion.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

As generally described herein, the present invention provides compoundsdesigned, for example, to act as GABA_(A) receptor modulators. Incertain embodiments, such compounds are envisioned to be useful astherapeutic agents for treating a CNS-related disorder (e.g., a disorderas described herein, for example depression, such as post-partumdepression or major depressive disorder).

Definitions

Chemical Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in ThomasSorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition,John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Isomers, e.g., stereoisomers, can be isolated from mixtures by methodsknown to those skilled in the art, including chiral high pressure liquidchromatography (HPLC) and the formation and crystallization of chiralsalts; or preferred isomers can be prepared by asymmetric syntheses.See, for example, Jacques et al., Enantiomers, Racemates and Resolutions(Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725(1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, N Y,1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind.1972). The invention additionally encompasses compounds described hereinas individual isomers substantially free of other isomers, andalternatively, as mixtures of various isomers.

“Stereoisomers”: It is also to be understood that compounds that havethe same molecular formula but differ in the nature or sequence ofbonding of their atoms or the arrangement of their atoms in space aretermed “isomers.” Isomers that differ in the arrangement of their atomsin space are termed “stereoisomers.” Stereoisomers that are not mirrorimages of one another are termed “diastereomers” and those that arenon-superimposable mirror images of each other are termed “enantiomers.”When a compound has an asymmetric center, for example, it is bonded tofour different groups, a pair of enantiomers is possible. An enantiomercan be characterized by the absolute configuration of its asymmetriccenter and is described by the R- and S-sequencing rules of Cahn andPrelog, or by the manner in which the molecule rotates the plane ofpolarized light and designated as dextrorotatory or levorotatory (i.e.,as (+) or (−)-isomers respectively). A chiral compound can exist aseither individual enantiomer or as a mixture thereof. A mixturecontaining equal proportions of the enantiomers is called a “racemicmixture”.

As used herein a pure enantiomeric compound is substantially free fromother enantiomers or stereoisomers of the compound (i.e., inenantiomeric excess). In other words, an “S” form of the compound issubstantially free from the “R” form of the compound and is, thus, inenantiomeric excess of the “R” form. The term “enantiomerically pure” or“pure enantiomer” denotes that the compound comprises more than 75% byweight, more than 80% by weight, more than 85% by weight, more than 90%by weight, more than 91% by weight, more than 92% by weight, more than93% by weight, more than 94% by weight, more than 95% by weight, morethan 96% by weight, more than 97% by weight, more than 98% by weight,more than 98.5% by weight, more than 99% by weight, more than 99.2% byweight, more than 99.5% by weight, more than 99.6% by weight, more than99.7% by weight, more than 99.8% by weight or more than 99.9% by weight,of the enantiomer. In certain embodiments, the weights are based upontotal weight of all enantiomers or stereoisomers of the compound.

In the compositions provided herein, an enantiomerically pure compoundcan be present with other active or inactive ingredients. For example, apharmaceutical composition comprising enantiomerically pureR-position/center/carbon compound can comprise, for example, about 90%excipient and about 10% enantiomerically pure R- compound. In certainembodiments, the enantiomerically pure R-compound in such compositionscan, for example, comprise, at least about 95% by weight R-compound andat most about 5% by weight S-compound, by total weight of the compound.For example, a pharmaceutical composition comprising enantiomericallypure S-compound can comprise, for example, about 90% excipient and about10% enantiomerically pure S-compound. In certain embodiments, theenantiomerically pure S-compound in such compositions can, for example,comprise, at least about 95% by weight S-compound and at most about 5%by weight R-compound, by total weight of the compound. In certainembodiments, the active ingredient can be formulated with little or noexcipient or carrier.

The term “diastereomierically pure” denotes that the compound comprisesmore than 75% by weight, more than 80% by weight, more than 85% byweight, more than 90% by weight, more than 91% by weight, more than 92%by weight, more than 93% by weight, more than 94% by weight, more than95% by weight, more than 96% by weight, more than 97% by weight, morethan 98% by weight, more than 98.5% by weight, more than 99% by weight,more than 99.2% by weight, more than 99.5% by weight, more than 99.6% byweight, more than 99.7% by weight, more than 99.8% by weight or morethan 99.9% by weight, of a single diastereomer. Methods for determiningdiastereomeric and enantiomeric purity are well-known in the art.Diastereomeric purity can be determined by any analytical method capableof quantitatively distinguishing between a compound and itsdiastereomers, such as high performance liquid chromatography (HPLC).

The articles “a” and “an” may be used herein to refer to one or to morethan one (i.e. at least one) of the grammatical objects of the article.By way of example “an analogue” means one analogue or more than oneanalogue.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

The following terms are intended to have the meanings presentedtherewith below and are useful in understanding the description andintended scope of the present invention.

“Alkyl” refers to a radical of a straight-chain or branched saturatedhydrocarbon group having from 1 to 20 carbon atoms (“C₁₋₂₀ alkyl”). Insome embodiments, an alkyl group has 1 to 12 carbon atoms (“C₁₋₁₂alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms(“C₁₋₁₀ alkyl”). In some embodiments, an alkyl group has 1 to 9 carbonatoms (“C₁₋₉ alkyl”). In some embodiments, an alkyl group has 1 to 8carbon atoms (“C₁₋₈ alkyl”). In some embodiments, an alkyl group has 1to 7 carbon atoms (“C₁₋₇ alkyl”). In some embodiments, an alkyl grouphas 1 to 6 carbon atoms (“C₁₋₆ alkyl”, also referred to herein as “loweralkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms(“C₁₋₅ alkyl”). In some embodiments, an alkyl group has 1 to 4 carbonatoms (“C₁₋₄ alkyl”). In some embodiments, an alkyl group has 1 to 3carbon atoms (“C₁₋₃ alkyl”). In some embodiments, an alkyl group has 1to 2 carbon atoms (“C₁₋₂ alkyl”). In some embodiments, an alkyl grouphas 1 carbon atom (“C₁ alkyl”). In some embodiments, an alkyl group has2 to 6 carbon atoms (“C₂₋₆ alkyl”). Examples of C₁₋₆ alkyl groupsinclude methyl (C₁), ethyl (C₂), n-propyl (C₃), isopropyl (C₃), n-butyl(C₄), tert-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), n-pentyl (C₅),3-pentanyl (C₅), amyl (C₅), neopentyl (C₅), 3-methyl-2-butanyl (C₅),tertiary amyl (C₅), and n-hexyl (C₆). Additional examples of alkylgroups include n-heptyl (C₇), n-octyl (C₈) and the like. Unlessotherwise specified, each instance of an alkyl group is independentlyoptionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”)or substituted (a “substituted alkyl”) with one or more substituents;e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1substituent. In certain embodiments, the alkyl group is unsubstitutedC₁₋₁₀ alkyl (e.g., —CH₃). In certain embodiments, the alkyl group issubstituted C₁₋₁₀ alkyl. Common alkyl abbreviations include Me (—CH₃),Et (—CH₂CH₃), iPr (—CH(CH₃)₂), nPr (—CH₂CH₂CH₃), n-Bu (—CH₂CH₂CH₂CH₃),or i-Bu (—CH₂CH(CH₃)₂).

“Alkylene” refers to an alkyl group wherein two hydrogens are removed toprovide a divalent radical, and which may be substituted orunsubstituted. Unsubstituted alkylene groups include, but are notlimited to, methylene (—CH₂—), ethylene (—CH₂CH₂—), propylene(—CH₂CH₂CH₂—), butylene (—CH₂CH₂CH₂CH₂—), pentylene (—CH₂CH₂CH₂CH₂CH₂—),hexylene (—CH₂CH₂CH₂CH₂CH₂CH₂—), and the like. Exemplary substitutedalkylene groups, e.g., substituted with one or more alkyl (methyl)groups, include but are not limited to, substituted methylene(—CH(CH₃)—, (—C(CH₃)₂—), substituted ethylene (—CH(CH₃)CH₂—,—CH₂CH(CH₃)—, —C(CH₃)₂CH₂—, —CH₂C(CH₃)₂—), substituted propylene(—CH(CH₃)CH₂CH₂—, —CH₂CH(CH₃)CH₂—, —CH₂CH₂CH(CH₃)—, —C(CH₃)₂CH₂CH₂—,—CH₂C(CH₃)₂CH₂—, —CH₂CH₂C(CH₃)₂—), and the like. When a range or numberof carbons is provided for a particular alkylene group, it is understoodthat the range or number refers to the range or number of carbons in thelinear carbon divalent chain. Alkylene groups may be substituted orunsubstituted with one or more substituents as described herein.

“Alkenyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon doublebonds), and optionally one or more carbon-carbon triple bonds (e.g., 1,2, 3, or 4 carbon-carbon triple bonds) (“C₂₋₂₀ alkenyl”). In certainembodiments, alkenyl does not contain any triple bonds. In someembodiments, an alkenyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms(“C₂₋₉ alkenyl”). In some embodiments, an alkenyl group has 2 to 8carbon atoms (“C₂₋₈ alkenyl”). In some embodiments, an alkenyl group has2 to 7 carbon atoms (“C₂₋₇ alkenyl”). In some embodiments, an alkenylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, analkenyl group has 2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In someembodiments, an alkenyl group has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”).In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C₂₋₃alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C₂alkenyl”). The one or more carbon-carbon double bonds can be internal(such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples ofC₂₋₄ alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl(C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and the like.Examples of C₂₋₆ alkenyl groups include the aforementioned C₂₋₄ alkenylgroups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and thelike. Additional examples of alkenyl include heptenyl (C₇), octenyl(C₈), octatrienyl (C₈), and the like. Unless otherwise specified, eachinstance of an alkenyl group is independently optionally substituted,i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a“substituted alkenyl”) with one or more substituents e.g., for instancefrom 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Incertain embodiments, the alkenyl group is unsubstituted C₂₋₁₀ alkenyl.In certain embodiments, the alkenyl group is substituted C₂₋₁₀ alkenyl.

“Alkynyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triplebonds), and optionally one or more carbon-carbon double bonds (e.g., 1,2, 3, or 4 carbon-carbon double bonds) (“C₂₋₂₀ alkynyl”). In certainembodiments, alkynyl does not contain any double bonds. In someembodiments, an alkynyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms(“C₂₋₉ alkynyl”). In some embodiments, an alkynyl group has 2 to 8carbon atoms (“C₂₋₈ alkynyl”). In some embodiments, an alkynyl group has2 to 7 carbon atoms (“C₂₋₇ alkynyl”). In some embodiments, an alkynylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkynyl”). In some embodiments, analkynyl group has 2 to 5 carbon atoms (“C₂₋₅ alkynyl”). In someembodiments, an alkynyl group has 2 to 4 carbon atoms (“C₂₋₄ alkynyl”).In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C₂₋₃alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C₂alkynyl”). The one or more carbon-carbon triple bonds can be internal(such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples ofC₂₋₄ alkynyl groups include, without limitation, ethynyl (C₂),1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), andthe like. Examples of C₂₋₆ alkenyl groups include the aforementionedC₂₋₄ alkynyl groups as well as pentynyl (C₅), hexynyl (C₆), and thelike. Additional examples of alkynyl include heptynyl (C₇), octynyl(C₈), and the like. Unless otherwise specified, each instance of analkynyl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted alkynyl”) or substituted (a“substituted alkynyl”) with one or more substituents; e.g., for instancefrom 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Incertain embodiments, the alkynyl group is unsubstituted C₂₋₁₀ alkynyl.In certain embodiments, the alkynyl group is substituted C₂₋₁₀ alkynyl.

The term “heteroalkyl,” as used herein, refers to an alkyl group, asdefined herein, which further comprises 1 or more (e.g., 1, 2, 3, or 4)heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus)within the parent chain, wherein the one or more heteroatoms is insertedbetween adjacent carbon atoms within the parent carbon chain and/or oneor more heteroatoms is inserted between a carbon atom and the parentmolecule, i.e., between the point of attachment. In certain embodiments,a heteroalkyl group refers to a saturated group having from 1 to 10carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC₁₋₁₀ alkyl”). Insome embodiments, a heteroalkyl group is a saturated group having 1 to 9carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC₁₋₉ alkyl”). In someembodiments, a heteroalkyl group is a saturated group having 1 to 8carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC₁₋₁₀ alkyl”). Insome embodiments, a heteroalkyl group is a saturated group having 1 to 7carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC₁₋₇ alkyl”). In someembodiments, a heteroalkyl group is a group having 1 to 6 carbon atomsand 1, 2, or 3 heteroatoms (“heteroC₁₋₆ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1or 2 heteroatoms (“heteroC₁_s alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms (“heteroC₁₋₄ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1heteroatom (“heteroC₁₋₃ alkyl”). In some embodiments, a heteroalkylgroup is a saturated group having 1 to 2 carbon atoms and 1 heteroatom(“heteroC₁₋₂ alkyl”). In some embodiments, a heteroalkyl group is asaturated group having 1 carbon atom and 1 heteroatom (“heteroC₁alkyl”). In some embodiments, a heteroalkyl group is a saturated grouphaving 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC₂₋₆ alkyl”).Unless otherwise specified, each instance of a heteroalkyl group isindependently unsubstituted (an “unsubstituted heteroalkyl”) orsubstituted (a “substituted heteroalkyl”) with one or more substituents.In certain embodiments, the heteroalkyl group is an unsubstitutedheteroC₁₋₁₀ alkyl. In certain embodiments, the heteroalkyl group is asubstituted heteroC₁₋₁₀ alkyl.

“Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclicor tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 πelectrons shared in a cyclic array) having 6-14 ring carbon atoms andzero heteroatoms provided in the aromatic ring system (“C₆₋₁₄ aryl”). Insome embodiments, an aryl group has six ring carbon atoms (“C₆ aryl”;e.g., phenyl). In some embodiments, an aryl group has ten ring carbonatoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). Insome embodiments, an aryl group has fourteen ring carbon atoms (“C₁₄aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein thearyl ring, as defined above, is fused with one or more carbocyclyl orheterocyclyl groups wherein the radical or point of attachment is on thearyl ring, and in such instances, the number of carbon atoms continue todesignate the number of carbon atoms in the aryl ring system. Typicalaryl groups include, but are not limited to, groups derived fromaceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene,benzene, chrysene, coronene, fluoranthene, fluorene, hexacene,hexaphene, hexalene, as-indacene, s-indacene, indane, indene,naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene,pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene,picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, andtrinaphthalene. Particularly aryl groups include phenyl, naphthyl,indenyl, and tetrahydronaphthyl. Unless otherwise specified, eachinstance of an aryl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted aryl”) or substituted (a “substitutedaryl”) with one or more substituents. In certain embodiments, the arylgroup is unsubstituted C₆₋₁₄ aryl. In certain embodiments, the arylgroup is substituted C₆₋₁₄ aryl.

In certain embodiments, an aryl group substituted with one or more ofgroups selected from halo, C₁-C₈ alkyl, C₁-C₈ haloalkyl, cyano, hydroxy,C₁-C₈ alkoxy, and amino.

Examples of representative substituted aryls include the following

wherein one of R⁵⁶ and R¹⁷ may be hydrogen and at least one of R¹⁶ andR¹⁷ is each independently selected from C₁-C₈ alkyl, C₁₋₅ haloalkyl,4-10 membered heterocyclyl, alkanoyl, C₁₋₅ alkoxy, heteroaryloxy,alkylamino, arylamino, heteroarylamino, NR⁵⁸COR⁵⁹, NR⁵⁸SOR⁵⁹NR⁵⁸SO₂R⁵⁹,COOalkyl, COOaryl, CONR⁵⁸R⁵⁹, CONR⁵⁸OR⁵⁹, NR⁵⁸R⁵⁹, SO₂NR⁵⁸R⁵⁹, S-alkyl,SOalkyl, SO₂alkyl, Saryl, SOaryl, SO₂aryl; or R⁵⁶ and R⁵⁷ may be joinedto form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms,optionally containing one or more heteroatoms selected from the group N,O, or S. R⁶⁰ and R⁶¹ are independently hydrogen, C₁-C₈ alkyl, C₁-C₄haloalkyl, C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₀ aryl,substituted C₆-C₁₀ aryl, 5-10 membered heteroaryl, or substituted 5-10membered heteroaryl.

“Fused aryl” refers to an aryl having two of its ring carbon in commonwith a second aryl or heteroaryl ring or with a carbocyclyl orheterocyclyl ring.

“Heteroaryl” refers to a radical of a 5-10 membered monocyclic orbicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electronsshared in a cyclic array) having ring carbon atoms and 1-4 ringheteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-10 membered heteroaryl”). In heteroaryl groups that contain one ormore nitrogen atoms, the point of attachment can be a carbon or nitrogenatom, as valency permits. Heteroaryl bicyclic ring systems can includeone or more heteroatoms in one or both rings. “Heteroaryl” includes ringsystems wherein the heteroaryl ring, as defined above, is fused with oneor more carbocyclyl or heterocyclyl groups wherein the point ofattachment is on the heteroaryl ring, and in such instances, the numberof ring members continue to designate the number of ring members in theheteroaryl ring system. “Heteroaryl” also includes ring systems whereinthe heteroaryl ring, as defined above, is fused with one or more arylgroups wherein the point of attachment is either on the aryl orheteroaryl ring, and in such instances, the number of ring membersdesignates the number of ring members in the fused (aryl/heteroaryl)ring system. Bicyclic heteroaryl groups wherein one ring does notcontain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and thelike) the point of attachment can be on either ring, i.e., either thering bearing a heteroatom (e.g., 2-indolyl) or the ring that does notcontain a heteroatom (e.g., 5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unlessotherwise specified, each instance of a heteroaryl group isindependently optionally substituted, i.e., unsubstituted (an“unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”)with one or more substituents. In certain embodiments, the heteroarylgroup is unsubstituted 5-14 membered heteroaryl. In certain embodiments,the heteroaryl group is substituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing one heteroatominclude, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary5-membered heteroaryl groups containing two heteroatoms include, withoutlimitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, andisothiazolyl. Exemplary 5-membered heteroaryl groups containing threeheteroatoms include, without limitation, triazolyl, oxadiazolyl, andthiadiazolyl. Exemplary 5-membered heteroaryl groups containing fourheteroatoms include, without limitation, tetrazolyl. Exemplary6-membered heteroaryl groups containing one heteroatom include, withoutlimitation, pyridinyl. Exemplary 6-membered heteroaryl groups containingtwo heteroatoms include, without limitation, pyridazinyl, pyrimidinyl,and pyrazinyl. Exemplary 6-membered heteroaryl groups containing threeor four heteroatoms include, without limitation, triazinyl andtetrazinyl, respectively. Exemplary 7-membered heteroaryl groupscontaining one heteroatom include, without limitation, azepinyl,oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groupsinclude, without limitation, indolyl, isoindolyl, indazolyl,benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl,benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl,indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groupsinclude, without limitation, naphthyridinyl, pteridinyl, quinolinyl,isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

Examples of representative heteroaryls include the following:

wherein each Z is selected from carbonyl, N, NR⁶⁵, O, and S; and R⁶⁵ isindependently hydrogen, C₁-C₈ alkyl, C₃-C₁₀ cycloalkyl, 4-10 memberedheterocyclyl, C₆-C₁₀ aryl, and 5-10 membered heteroaryl.

“Carbocyclyl” or “carbocyclic” refers to a radical of a non-aromaticcyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C₃₋₁₀carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. Insome embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms(“C₃₋₈ carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to6 ring carbon atoms (“C₃₋₆ carbocyclyl”). In some embodiments, acarbocyclyl group has 3 to 6 ring carbon atoms (“C₃₋₆ carbocyclyl”). Insome embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms(“C₅₋₁₀ carbocyclyl”). Exemplary C₃_₆ carbocyclyl groups include,without limitation, cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl(C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅),cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like.Exemplary C₃₋₈ carbocyclyl groups include, without limitation, theaforementioned C₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇),cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇),bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C₃₋₁₀ carbocyclylgroups include, without limitation, the aforementioned C₃₋₈ carbocyclylgroups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀),cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl(C₁₀), spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged orspiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) andcan be saturated or can be partially unsaturated. “Carbocyclyl” alsoincludes ring systems wherein the carbocyclyl ring, as defined above, isfused with one or more aryl or heteroaryl groups wherein the point ofattachment is on the carbocyclyl ring, and in such instances, the numberof carbons continue to designate the number of carbons in thecarbocyclic ring system. Unless otherwise specified, each instance of acarbocyclyl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents. In certainembodiments, the carbocyclyl group is unsubstituted C₃₋₁₀ carbocyclyl.In certain embodiments, the carbocyclyl group is a substituted C₃₋₁₀carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 10 ring carbon atoms (“C₃₋₁₀cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ringcarbon atoms (“C₃₋₈ cycloalkyl”). In some embodiments, a cycloalkylgroup has 3 to 6 ring carbon atoms (“C₃₋₆ cycloalkyl”). In someembodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C₅₋₆cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ringcarbon atoms (“C₅₋₁₀ cycloalkyl”). Examples of C₅₋₆ cycloalkyl groupsinclude cyclopentyl (C₅) and cyclohexyl (C₅). Examples of C₃₋₄cycloalkyl groups include the aforementioned C₅₋₆ cycloalkyl groups aswell as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C₃₋₈cycloalkyl groups include the aforementioned C₃₋₆ cycloalkyl groups aswell as cycloheptyl (C₇) and cyclooctyl (C₈). Unless otherwisespecified, each instance of a cycloalkyl group is independentlyunsubstituted (an “unsubstituted cycloalkyl”) or substituted (a“substituted cycloalkyl”) with one or more substituents. In certainembodiments, the cycloalkyl group is unsubstituted C₃₋₁₀ cycloalkyl. Incertain embodiments, the cycloalkyl group is substituted C₃₋₁₀cycloalkyl.

“Heterocyclyl” or “heterocyclic” refers to a radical of a 3- to10-membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 memberedheterocyclyl”). In heterocyclyl groups that contain one or more nitrogenatoms, the point of attachment can be a carbon or nitrogen atom, asvalency permits. A heterocyclyl group can either be monocyclic(“monocyclic heterocyclyl”) or a fused, bridged or spiro ring systemsuch as a bicyclic system (“bicyclic heterocyclyl”), and can besaturated or can be partially unsaturated. Heterocyclyl bicyclic ringsystems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclyl ring,as defined above, is fused with one or more carbocyclyl groups whereinthe point of attachment is either on the carbocyclyl or heterocyclylring, or ring systems wherein the heterocyclyl ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment is on the heterocyclyl ring, and in such instances, thenumber of ring members continue to designate the number of ring membersin the heterocyclyl ring system. Unless otherwise specified, eachinstance of heterocyclyl is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a“substituted heterocyclyl”) with one or more substituents. In certainembodiments, the heterocyclyl group is unsubstituted 3-10 memberedheterocyclyl. In certain embodiments, the heterocyclyl group issubstituted 3-10 membered heterocyclyl.

In some embodiments, a heterocyclyl group is a 5-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 memberedheterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8membered non-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-6 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-6 membered heterocyclyl”). In some embodiments, the 5-6 memberedheterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen,and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2ring heteroatoms selected from nitrogen, oxygen, and sulfur. In someembodiments, the 5-6 membered heterocyclyl has one ring heteroatomselected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing one heteroatominclude, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary4-membered heterocyclyl groups containing one heteroatom include,without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary5-membered heterocyclyl groups containing one heteroatom include,without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyland pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, dioxolanyl,oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-memberedheterocyclyl groups containing three heteroatoms include, withoutlimitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary6-membered heterocyclyl groups containing one heteroatom include,without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl,and thianyl. Exemplary 6-membered heterocyclyl groups containing twoheteroatoms include, without limitation, piperazinyl, morpholinyl,dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containingtwo heteroatoms include, without limitation, triazinanyl. Exemplary7-membered heterocyclyl groups containing one heteroatom include,without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary8-membered heterocyclyl groups containing one heteroatom include,without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary5-membered heterocyclyl groups fused to a C₆ aryl ring (also referred toherein as a 5,6-bicyclic heterocyclic ring) include, without limitation,indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groupsfused to an aryl ring (also referred to herein as a 6,6-bicyclicheterocyclic ring) include, without limitation, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and the like.

“Nitrogen-containing heterocyclyl” group means a 4- to 7-memberednon-aromatic cyclic group containing at least one nitrogen atom, forexample, but without limitation, morpholine, piperidine (e.g.2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g.2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline,imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazines such as N-methyl piperazine. Particular examples includeazetidine, piperidone and piperazone.

“Hetero” when used to describe a compound or a group present on acompound means that one or more carbon atoms in the compound or grouphave been replaced by a nitrogen, oxygen, or sulfur heteroatom. Heteromay be applied to any of the hydrocarbyl groups described above such asalkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g,.heteroaryl, cycloalkenyl, e.g,. cycloheteroalkenyl, and the like havingfrom 1 to 5, and particularly from 1 to 3 heteroatoms.

“Acyl” refers to a radical —C(O)R²⁰, where R²⁰ is hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl, asdefined herein. “Alkanoyl” is an acyl group wherein R²⁰ is a group otherthan hydrogen. Representative acyl groups include, but are not limitedto, formyl (—CHO), acetyl (—C(═O)CH₃), cyclohexylcarbonyl,cyclohexylmethylcarbonyl, benzoyl (—C(═O)Ph), benzylcarbonyl(—C(═O)CH₂Ph), C(O)—C₁₋₅ alkyl, —C(O)—(CH₂)_(t)(C₆-C₁₀ aryl),—C(O)—(CH₂)_(t)(5-10 membered heteroaryl), —C(O)—(CH₂)_(t)(C₃₋₁₀cycloalkyl), and —C(O)—(CH₂)_(t)(4-10 membered heterocyclyl), wherein tis an integer from 0 to 4. In certain embodiments, R²¹ is C₁-C₈ alkyl,substituted with halo or hydroxy; or C₃-C₁₀ cycloalkyl, 4-10 memberedheterocyclyl, C₆-C₁₀ aryl, arylalkyl, 5-10 membered heteroaryl orheteroarylalkyl, each of which is substituted with unsubstituted C₁-C₄alkyl, halo, unsubstituted C₁-C₄ alkoxy, unsubstituted C₁-C₄ haloalkyl,unsubstituted C₁-C₄ hydroxyalkyl, or unsubstituted C₁-C₄ haloalkoxy orhydroxy.

“Alkoxy” refers to the group —OR²⁹ where R²⁹ is substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl. Particular alkoxygroups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6carbon atoms. Further particular alkoxy groups have between 1 and 4carbon atoms.

In certain embodiments, R²⁹ is a group that has 1 or more substituents,for instance from 1 to 5 substituents, and particularly from 1 to 3substituents, in particular 1 substituent, selected from the groupconsisting of amino, substituted amino, C₆-C₁₀ aryl, aryloxy, carboxyl,cyano, C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol,alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂- and aryl-S(O)₂-. Exemplary‘substituted alkoxy’ groups include, but are not limited to,—O—(CH₂)_(t)(C₆-C₁₀ aryl), —O—(CH₂)_(t)(5-10 membered heteroaryl),—O—(CH₂)_(t)(C₃-C₁₀ cycloalkyl), and —O—(CH₂)_(t)(4-10 memberedheterocyclyl), wherein t is an integer from 0 to 4 and any aryl,heteroaryl, cycloalkyl or heterocyclyl groups present, may themselves besubstituted by unsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl,or unsubstituted C₁-C₄ haloalkoxy or hydroxy. Particular exemplary‘substituted alkoxy’ groups are —OCF₃, —OCH₂CF₃, —OCH₂Ph,—OCH₂-cyclopropyl, —OCH₂CH₂OH, and —OCH₂CH₂NMe₂.

“Amino” refers to the radical —NH₂.

“Oxo group” refers to —C(═O)—.

“Substituted amino” refers to an amino group of the formula —N(R³⁸)₂wherein R³⁸ is hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted carbocyclyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, or an amino protecting group, wherein at leastone of R³⁸ is not a hydrogen. In certain embodiments, each R³⁸ isindependently selected from hydrogen, C₁-C₈ alkyl, C₃-C₈ alkenyl, C₃-C₈alkynyl, C₆-C₁₀ aryl, 5-10 membered heteroaryl, 4-10 memberedheterocyclyl, or C₃-C₁₀ cycloalkyl; or C₁-C₈ alkyl, substituted withhalo or hydroxy; C₃-C₈ alkenyl, substituted with halo or hydroxy; C₃-C₈alkynyl, substituted with halo or hydroxy, or —(CH₂)_(t)(C₆-C₁₀ aryl),—(CH₂)_(t)(5-10 membered heteroaryl), —(CH₂)_(t)(C₃-C₁₀ cycloalkyl), or—(CH₂)_(t)(4-10 membered heterocyclyl), wherein t is an integer between0 and 8, each of which is substituted by unsubstituted C₁-C₄ alkyl,halo, unsubstituted C₁-C₄ alkoxy, unsubstituted C₁-C₄ haloalkyl,unsubstituted C₁-C₄ hydroxyalkyl, or unsubstituted C₁-C₄ haloalkoxy orhydroxy; or both R³⁸ groups are joined to form an alkylene group.

Exemplary “substituted amino” groups include, but are not limited to,—NR³⁹—C₁₋₅ alkyl, —NR³⁹—(CH₂)_(t)(C₆-C₁₀ aryl), —NR³⁹—(CH₂)_(t)(5-10membered heteroaryl), —NR³⁹—(CH₂)_(t)(C₃—C₁₀ cycloalkyl), and—NR³⁹—(CH₂)_(t)(4-10 membered heterocyclyl), wherein t is an integerfrom 0 to 4, for instance 1 or 2, each R³⁹ independently represents H orC₁-C₈ alkyl; and any alkyl groups present, may themselves be substitutedby halo, substituted or unsubstituted amino, or hydroxy; and any aryl,heteroaryl, cycloalkyl, or heterocyclyl groups present, may themselvesbe substituted by unsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl,or unsubstituted C₁-C₄ haloalkoxy or hydroxy. For the avoidance of doubtthe term ‘substituted amino’ includes the groups alkylamino, substitutedalkylamino, alkylarylamino, substituted alkylarylamino, arylamino,substituted arylamino, dialkylamino, and substituted dialkylamino asdefined below. Substituted amino encompasses both monosubstituted aminoand disubstituted amino groups.

“Carboxy” refers to the radical —C(O)OH.

“Cyano” refers to the radical —CN.

“Halo” or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), andiodo (I). In certain embodiments, the halo group is either fluoro orchloro.

“Haloalkyl” refers to an alkyl radical in which the alkyl group issubstituted with one or more halogens. Typical haloalkyl groups include,but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl,chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl,tetrafluoroethyl, and the like.

“Hydroxy” refers to the radical —OH.

“Nitro” refers to the radical —NO₂.

“Thioketo” refers to the group ═S.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylgroups, as defined herein, are optionally substituted (e.g.,“substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted”alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or“unsubstituted” carbocyclyl, “substituted” or “unsubstituted”heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or“unsubstituted” heteroaryl group). In general, the term “substituted”,whether preceded by the term “optionally” or not, means that at leastone hydrogen present on a group (e.g., a carbon or nitrogen atom) isreplaced with a permissible substituent, e.g., a substituent which uponsubstitution results in a stable compound, e.g., a compound which doesnot spontaneously undergo transformation such as by rearrangement,cyclization, elimination, or other reaction. Unless otherwise indicated,a “substituted” group has a substituent at one or more substitutablepositions of the group, and when more than one position in any givenstructure is substituted, the substituent is either the same ordifferent at each position. The term “substituted” is contemplated toinclude substitution with all permissible substituents of organiccompounds, any of the substituents described herein that results in theformation of a stable compound. The present invention contemplates anyand all such combinations in order to arrive at a stable compound. Forpurposes of this invention, heteroatoms such as nitrogen may havehydrogen substituents and/or any suitable substituent as describedherein which satisfy the valencies of the heteroatoms and results in theformation of a stable moiety.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa),—SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa),—S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃,—OSi(R^(aa))₃—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa),—SC(═S)SR^(aa), —SC(═O)SR^(aa), —OC(═O)SR^(aa), —SC(═O)OR^(aa),—SC(═O)R^(aa), —P(═O)₂R^(aa), —OP(═O)₂R^(aa), —P(═O)(R^(aa))₂,—OP(═O)(R^(aa))₂, —OP(═O)(OR^(aa))₂, —P(═O)₂N(R^(bb))₂,—OP(═O)₂N(R^(bb))₂, —P(═O)(NR^(bb))₂, —OP(═O)(NR^(bb))₂,—NR^(bb)P(═O)(OR^(aa))₂, —NR^(bb)P(═O)(NR^(bb))₂, —P(R^(cc))₂,—P(R^(cc))₃, —OP(R^(cc))₂, —OP(R^(cc))₃, —B(R^(aa))₂, —B(OR^(cc))₂,—BR^(aa)(OR^(cc)), C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups; or two geminalhydrogens on a carbon atom are replaced with the group ═O, ═S,═NN(R^(bb))₂, —NNR^(bb)C(═O)R^(aa), ═NNR^(bb)C(═O)OR^(aa),—NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or ═NOR^(cc);

each instance of R^(aa) is, independently, selected from C₁₋₁₀ alkyl,C₁₋₁₀ haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or twoR^(aa) groups are joined to form a 3-14 membered heterocyclyl or 5-14membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(bb) is, independently, selected from hydrogen, —OH,—OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂,—SO₂R^(cc), —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc),—C(═S)SR^(cc), —P(═O)₂R^(aa), —P(═O)(Ra)₂, —P(═O)₂N(R^(cc))₂,—P(═O)(NR^(cc))₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14 membered heteroaryl, or two R^(bb) groups are joined to form a 3-14membered heterocyclyl or 5-14 membered heteroaryl ring, wherein eachalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylis independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of RC is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, ortwo R^(cc) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(dd) is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(ff))₂,—N(R^(ff))₃ ⁺X⁻, —N(OR^(ee))R^(ff), —SH, —SR^(ee), —SSR^(ee),—C(═O)R^(ee), —CO₂H, —CO₂R^(ee), —OC(═O)R^(ee), —OCO₂R^(ee),—C(═O)N(R^(ff))₂, —OC(═O)N(R^(ff))₂, —NR^(ff)C(═O)R^(ee),—NR^(ff)CO₂R^(ee), —NR^(ff)C(═O)N(R^(ff))₂, —C(═NR^(ff))OR^(ee),—OC(═NR^(ff))R^(ee), —OC(═NR^(ff))OR^(ee), —C(═NR^(ff))N(R^(ff))₂,—OC(═NR^(ff))N(R^(ff))₂, —NR^(ff)C(═NR^(ff))N(R^(ff))₂,—NR^(ff)SO₂R^(ee), —SO₂N(R^(ff))₂, —SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee),—S(═O)R^(ee), —Si(R^(ee))₃, —OSi(R^(ee))₃, —C(═S)N(R^(ff))₂,—C(═O)SR^(ee), —C(═S)SR^(ee), —SC(═S)SR^(ee), —P(═O)₂R^(ee),—P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂—OP(═O)(OR^(ee))₂, C₁_alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, 3-10 memberedheterocyclyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups, or twogeminal R^(dd) substituents can be joined to form ═O or ═S;

each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups;

each instance of R^(f) is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl,3-10 membered heterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, ortwo R^(f) groups are joined to form a 3-14 membered heterocyclyl or 5-14membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups; and

each instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂,—N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆ alkyl)⁺X⁻, —NH₃⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH,—SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂,—NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl),—OC(NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl,—SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃,—OSi(C₁₋₆ alkyl)₃ —C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂,—C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)₂(C₁₋₆alkyl), —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆alkyl)₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 memberedheteroaryl; or two geminal R⁹⁹ substituents can be joined to form ═O or═S; wherein X⁻ is a counterion.

A “counterion” or “anionic counterion” is a negatively charged groupassociated with a cationic quaternary amino group in order to maintainelectronic neutrality. Exemplary counterions include halide ions (e.g.,F⁻, Cl⁻, Br⁻, I⁻), NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻, HSO₄ ⁻, sulfonate ions(e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate,benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate,naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonicacid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate,ethanoate, propanoate, benzoate, glycerate, lactate, tartrate,glycolate, and the like).

These and other exemplary substituents are described in more detail inthe Detailed Description, and Claims. The invention is not intended tobe limited in any manner by the above exemplary listing of substituents.

Other Definitions

As used herein, the term “modulation” refers to the inhibition orpotentiation of GABA_(A) receptor function. A “modulator” (e.g., amodulator compound) may be, for example, an agonist, partial agonist,antagonist, or partial antagonist of the GABA_(A) receptor.

“Pharmaceutically acceptable” means approved or approvable by aregulatory agency of the Federal or a state government or thecorresponding agency in countries other than the United States, or thatis listed in the U.S. Pharmacopoeia or other generally recognizedpharmacopoeia for use in animals, and more particularly, in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound of theinvention that is pharmaceutically acceptable and that possesses thedesired pharmacological activity of the parent compound. In particular,such salts are non-toxic may be inorganic or organic acid addition saltsand base addition salts. Specifically, such salts include: (1) acidaddition salts, formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike; or formed with organic acids such as acetic acid, propionic acid,hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike. Salts further include, by way of example only, sodium, potassium,calcium, magnesium, ammonium, tetraalkylammonium, and the like; and whenthe compound contains a basic functionality, salts of non-toxic organicor inorganic acids, such as hydrochloride, hydrobromide, tartrate,mesylate, acetate, maleate, oxalate and the like. The term“pharmaceutically acceptable cation” refers to an acceptable cationiccounter-ion of an acidic functional group. Such cations are exemplifiedby sodium, potassium, calcium, magnesium, ammonium, tetraalkylammoniumcations, and the like. See, e.g., Berge, et al., J. Pharm. Sci. (1977)66(1): 1-79.

The term “prodrug” is intended to encompass therapeutically inactivecompounds that, under physiological conditions, are converted into thetherapeutically active agents of the present invention. One method formaking a prodrug is to design selected moieties that are hydrolyzed orcleaved at a targeted in vivo site of action under physiologicalconditions to reveal the desired molecule which then produces itstherapeutic effect. In certain embodiments, the prodrug is converted byan enzymatic activity of the subject.

In an alternate embodiment, the present invention provides prodrugs ofcompound of Formula (I), wherein the prodrug includes a cleavable moietyon the C3 hydroxy as depicted in Formula (I).

“Tautomers” refer to compounds that are interchangeable forms of aparticular compound structure, and that vary in the displacement ofhydrogen atoms and electrons. Thus, two structures may be in equilibriumthrough the movement of π electrons and an atom (usually H). Forexample, enols and ketones are tautomers because they are rapidlyinterconverted by treatment with either acid or base. Another example oftautomerism is the aci- and nitro- forms of phenylnitromethane, that arelikewise formed by treatment with acid or base. Tautomeric forms may berelevant to the attainment of the optimal chemical reactivity andbiological activity of a compound of interest.

A “subject” to which administration is contemplated includes, but is notlimited to, humans (i.e., a male or female of any age group, e.g., apediatric subject (e.g, infant, child, adolescent) or adult subject(e.g., young adult, middle-aged adult or senior adult)) and/or anon-human animal, e.g., a mammal such as primates (e.g., cynomolgusmonkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents,cats, and/or dogs. In certain embodiments, the subject is a human(“human subject”). In certain embodiments, the subject is a non-humananimal.

In certain embodiments, the substituent present on an oxygen atom is anoxygen protecting group (also referred to as a hydroxyl protectinggroup). Oxygen protecting groups include, but are not limited to,—R^(aa), —N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa),—C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃,—P(R^(cc))₂, —P(R^(cc))₃, —P(═O)₂R^(aa),—P(═O)(R^(aa))₂—P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and—P(═O)(NR^(bb))₂, wherein R^(aa), R^(bb), and R^(cc) are as definedherein. Oxygen protecting groups are well known in the art and includethose described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999,incorporated herein by reference.

Exemplary oxygen protecting groups include, but are not limited to,methyl, methoxylmethyl (MOM), 2-methoxyethoxymethyl (MEM), benzyl (Bn),triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBDMS),t-butylmethoxyphenylsilyl (TBMPS), methanesulfonate (mesylate), andtosylate (Ts).

In certain embodiments, the substituent present on a sulfur atom is asulfur protecting group (also referred to as a thiol protecting group).Sulfur protecting groups include, but are not limited to, —R^(aa),—N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa), —C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂,—S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃, —P(R^(cc))₂, —P(R^(cc))₃,—P(═O)₂R^(aa), —P(═O)(R^(aa)), —P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and—P(═O)(NR^(bb))₂, wherein Ra, R^(bb), and R^(cc) are as defined herein.Sulfur protecting groups are well known in the art and include thosedescribed in detail in Protecting Groups in Organic Synthesis, T. W.Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999,incorporated herein by reference.

In certain embodiments, the substituent present on a nitrogen atom is anamino protecting group (also referred to herein as a nitrogen protectinggroup). Amino protecting groups include, but are not limited to, —OH,—OR^(aa), —N(R^(cc)), —C(═O)R^(aa), —C(═O)OR^(aa), —C(═O)N(R^(cc)),—S(═O)₂R^(aa), —C(═NRC)R, —C(═NR^(cc))OR^(aa), —C(═NR)N(R^(cc)),—SO₂N(R^(aa))₂, —SO₂R^(cc), —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc)),—C(═O)SR^(cc), —C(═S)SR^(cc), C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,C₃₋₁₀ carbocyclyl, 3-14-membered heterocyclyl, C₆₋₁₄ aryl, and5-14-membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups, and wherein R^(aa),R^(bb), R^(cc) and R^(dd) are as defined herein. Amino protecting groupsare well known in the art and include those described in detail inProtecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts,3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

Exemplary amino protecting groups include, but are not limited to amidegroups (e.g., —C(═O)R^(aa)), which include, but are not limited to,formamide and acetamide; carbamate groups (e.g., —C(═O)OR^(aa)), whichinclude, but are not limited to, 9-fluorenylmethyl carbamate (Fmoc),t-butyl carbamate (BOC), and benzyl carbamate (Cbz); sulfonamide groups(e.g., —S(═O)₂R^(aa)) which include, but are not limited to,p-toluenesulfonamide (Ts), methanesulfonamide (Ms), andN-[2-(trimethylsilyl)ethoxy]methylamine (SEM).

Disease, disorder, and condition are used interchangeably herein.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” contemplate an action that occurs while asubject is suffering from the specified disease, disorder or condition,which reduces the severity of the disease, disorder or condition, orretards or slows the progression of the disease, disorder or condition(“therapeutic treatment”), and also contemplates an action that occursbefore a subject begins to suffer from the specified disease, disorderor condition.

In general, the “effective amount” of a compound refers to an amountsufficient to elicit the desired biological response, e.g., to treat aCNS-related disorder, is sufficient to induce anesthesia or sedation. Aswill be appreciated by those of ordinary skill in this art, theeffective amount of a compound of the invention may vary depending onsuch factors as the desired biological endpoint, the pharmacokinetics ofthe compound, the disease being treated, the mode of administration, andthe age, weight, health, and condition of the subject.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment of a disease, disorder orcondition, or to delay or minimize one or more symptoms associated withthe disease, disorder or condition. A therapeutically effective amountof a compound means an amount of therapeutic agent, alone or incombination with other therapies, which provides a therapeutic benefitin the treatment of the disease, disorder or condition. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease orcondition, or enhances the therapeutic efficacy of another therapeuticagent.

In an alternate embodiment, the present invention contemplatesadministration of the compounds of the present invention or apharmaceutically acceptable salt or a pharmaceutically acceptablecomposition thereof, as a prophylactic before a subject begins to sufferfrom the specified disease, disorder or condition. As used herein, andunless otherwise specified, a “prophylactically effective amount” of acompound is an amount sufficient to prevent a disease, disorder orcondition, or one or more symptoms associated with the disease, disorderor condition, or prevent its recurrence. A prophylactically effectiveamount of a compound means an amount of a therapeutic agent, alone or incombination with other agents, which provides a prophylactic benefit inthe prevention of the disease, disorder or condition. The term“prophylactically effective amount” can encompass an amount thatimproves overall prophylaxis or enhances the prophylactic efficacy ofanother prophylactic agent.

As used herein, an “episodic dosing regimen” is a dosing regimen whereina compound of Formula (I) or a composition comprising a compound ofFormula (I) is administered to a subject for a finite period of time inresponse to the diagnosis of a disorder or symptom thereof, e.g, adiagnosis or symptom of depression. an episode of major depressivedisorder, bipolar depression, anxiety, or postpartum depression. In someembodiments, the major depressive disorder is moderate major depressivedisorder. In some embodiments, the major depressive disorder is severemajor depressive disorder. In some embodiments, the compound isformulated as individual dosage units, each unit comprising a compoundof Formula (I) and one or more suitable pharmaceutical excipients. Insome embodiments, the episodic dosing regimen has a duration of aplurality of weeks, e.g. about 8 weeks. In contrast with chronicadministration as defined herein, episodic dosing of a compound occursover a finite period of time, e.g., from about 2 weeks to about 8 weeks,in response to a diagnosis of a disorder, e.g., depression, or a symptomthereof. In some embodiments, episodic dosing occurs once per day acrossa plurality of weeks, e.g., from about 2 weeks to about 6 weeks. In oneembodiment, the episodic dosing has a duration of two weeks. In someembodiments, more than one episodic dosing regimen is administered tothe subject, e.g., two or more episodic regimens throughout thesubject's life.

Compounds

It should be appreciated that formulas described herein may referenceparticular carbon atoms, such as C17, C3, C19, etc. These references arebased on the position of carbon atoms according to steroid nomenclatureknown and used in the industry, as shown below:

For example, C17 refers to the carbon at position 17 and C3 refers tothe carbon at position 3.

In an aspect, provided herein is a compound of Formula (I):

or a pharmaceutically acceptable salt thereof;wherein:

-   -   represents a single or double bond, provided if a double bond is        present, then one of R^(6a) or R^(6b) is absent and R⁵ is        absent;    -   R^(X) is selected from the group consisting of halo, —CN, —OH,        —OR^(Q1), and substituted or unsubstituted alkyl, wherein R^(Q1)        is substituted or unsubstituted alkyl;    -   R^(Y) is halo or substituted or unsubstituted alkyl; or    -   R^(Y) and R^(X) may join together with the intervening atoms to        form a substituted or unsubstituted carbocyclyl or a substituted        or unsubstituted heterocyclyl;    -   R³ is selected from the group consisting of substituted or        unsubstituted alkyl, substituted or unsubstituted alkenyl,        substituted or unsubstituted alkynyl, substituted or        unsubstituted carbocyclyl, substituted or unsubstituted        heterocyclyl, substituted or unsubstituted aryl, and substituted        or unsubstituted heteroaryl;    -   R⁵ is hydrogen or methyl;    -   each instance of R²² is independently selected from the group        consisting of halogen, —NO₂, —CN, —OR^(GA), —N(R^(GA))₂,        —C(═O)R^(GA), —C(═O)OR^(GA), —OC(═O)R^(GA), —OC(═O)OR^(GA),        —C(═O)N(R^(GA))₂, —N(R^(GA))C(═O)R^(GA), —OC(═O)N(R^(GA))₂,        —N(R^(GA))C(═O)OR^(GA), —N(R^(GA))C(═O)N(R^(GA))₂, —SR^(GA),        —S(═O) R^(GA), —S(═O)₂R^(GA), —S(═O)₂OR^(GA), —OS(═O)₂R^(GA),        —S(═O)₂N(R^(GA))₂, —N(R^(GA))S(═O)₂R^(GA), substituted or        unsubstituted alkyl, substituted or unsubstituted alkenyl,        substituted or unsubstituted alkynyl, substituted or        unsubstituted carbocylyl, substituted or unsubstituted        heterocyclyl, substituted or unsubstituted aryl, and substituted        or unsubstituted heteroaryl, wherein each instance of R^(GA) is        independently selected from the group consisting of hydrogen,        substituted or unsubstituted C₁₋₆ alkyl, substituted or        unsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆        alkynyl, substituted or unsubstituted C₃-s carbocylyl,        substituted or unsubstituted 3- to 6-membered heterocyclyl,        substituted or unsubstituted aryl, substituted or unsubstituted        heteroaryl, an oxygen protecting group when attached to oxygen,        and a nitrogen protecting group when attached to nitrogen, or        two R^(GA) groups are taken with the intervening atoms to form a        substituted or unsubstituted heterocyclyl or heteroaryl ring;    -   each of R^(1a), R^(1b), R^(2a), R^(2b), R^(4a), R^(4b), R^(7a),        R^(7b), R^(11a), R^(11b), R^(12a), and R^(12b) is independently        selected from the group consisting of hydrogen, halogen, cyano,        —NO₂, substituted or unsubstituted alkyl, substituted or        unsubstituted alkenyl, substituted or unsubstituted alkynyl,        substituted or unsubstituted carbocyclyl, substituted or        unsubstituted heterocyclyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl, —OR^(A1), —N(R^(A1))₂,        —SR^(A1), —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)SR^(A1),        —C(═O)N(R^(A1))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1),        —OC(═O)N(R^(A1))₂, —OC(═O)SR^(A1), —OS(═O)₂R^(A1),        —OS(═O)₂OR^(A1), —OS(═O)₂N(R^(A1))₂, —N(R^(A1))C(═O)R^(A1),        —N(R^(A1))C(═NR^(A1))R^(A1), —N(R^(A1))C(═O)OR^(A1),        —N(R^(A1))C(═O)N(R^(A1))₂, —N(R^(A1))C(═NR^(A1)) N(R^(A1))₂,        —N(R^(A1))S(═O)₂R^(A1), —N(R^(A1))S(═O)₂OR^(A1),        —N(R^(A1))S(═O)₂N(R^(A1))₂, —SC(═O)R^(A1), —SC(═O)OR^(A1),        —SC(═O)SR^(A1), —SC(═O)N(R^(A1))₂, —S(═O)₂R^(A1),        —S(═O)₂OR^(A1), or —S(═O)₂N(R^(A1))₂, wherein each instance of        R^(A1) is independently selected from the group consisting of        hydrogen, substituted or unsubstituted C₁₋₆alkyl, substituted or        unsubstituted C₂₋₆alkenyl, substituted or unsubstituted C₂₋₆        alkynyl, substituted or unsubstituted C₃₋₆carbocyclyl, or        substituted or unsubstituted 3- to 6-membered heterocyclyl,        substituted or unsubstituted aryl, substituted or unsubstituted        heteroaryl, an oxygen protecting group when attached to oxygen,        a nitrogen protecting group when attached to nitrogen, and a        sulfur protecting group when attached to sulfur, or two R^(A1)        groups are taken with the intervening atoms to form a        substituted or unsubstituted heterocyclic ring;    -   each of R^(6a) and R^(6b) is independently selected from the        group consisting of hydrogen, halogen, cyano, —NO₂, —OH,        substituted or unsubstituted alkyl, substituted or unsubstituted        alkenyl, and substituted or unsubstituted alkynyl; or R^(6a) and        R^(6b) are joined to form an oxo (═O) group;    -   each of R^(15a), R^(15b), R^(16a), and R^(16b) is independently        selected from the group consisting of hydrogen, halogen, —CN,        —NO₂, substituted or unsubstituted alkyl, substituted or        unsubstituted alkenyl, substituted or unsubstituted alkynyl,        substituted or unsubstituted carbocyclyl, substituted or        unsubstituted heterocyclyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl, —OR^(C3), —N(R^(C3))₂,        —SR^(C3), —C(═O)R^(C3), —C(═O)OR^(C3), —C(═O)SR^(C3),        —C(═O)N(R^(C3))₂, —OC(═O)R^(C3), —OC(═O)OR^(C3),        —OC(═O)N(R^(C3))₂, —OC(═O)SR^(C3), —OS(═O)₂R^(C3),        —OS(═O)₂OR^(C3), —OS(═O)₂N(R^(C3))₂, —N(R^(C3))C(═O)R^(C3),        —N(R^(C3))C(═NR^(C3))R^(C3), —N(R^(C3))C(═O)OR^(C3),        —N(R^(C3))C(═O)N(R^(C3))₂, —N(R^(C3))C(═NR^(C3)) N(R^(C3))₂,        —N(R^(C3))S(═O)₂R^(C3), —N(R^(C3))S(═O)₂OR^(C3),        —N(R^(C3))S(═O)₂N(R^(C3))₂, —SC(═O)R^(C3), —SC(═O)OR^(C3),        —SC(═O)SR^(C3), —SC(═O)N(R^(C3))₂, —S(═O)₂R^(C3),        —S(═O)₂OR^(C3), or —S(═O)₂N(R^(C3))₂, wherein each instance of        R^(C3) is independently selected from the group consisting of        hydrogen, substituted or unsubstituted C₁₋₆alkyl, substituted or        unsubstituted C₂₋₆alkenyl, substituted or unsubstituted        C₂₋₆alkynyl, substituted or unsubstituted aryl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted        carbocyclyl, or substituted or unsubstituted heterocyclyl, an        oxygen protecting group when attached to oxygen, a nitrogen        protecting group when attached to nitrogen, and a sulfur        protecting group when attached to sulfur, or two R^(C3) groups        are taken with the intervening atoms to form a substituted or        unsubstituted heterocyclic ring;    -   R¹⁹ is hydrogen or substituted or unsubstituted alkyl; and    -   n is selected from the group consisting of 0, 1, 2, and 3.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-a), Formula (I-b), Formula (I-c1), Formula (I-c2), Formula(I-d1), Formula (I-d2), Formula (I-e1), Formula (I-e2), Formula (I-e3),Formula (I-e4), Formula (I-b 1), Formula (I-c3), Formula (I-c4), Formula(I-d3), Formula (I-d4), Formula (I-e5), Formula (I-e6), Formula (I-e7),or Formula (I-e8).

In some embodiments, the compound of Formula I is a compound of FormulaI-a:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (I) and eachR^(1a), R^(1b), R^(2a), R^(2b), R^(4a), R^(4b), R^(7a), R^(7b), R^(11a),R^(11b), R^(12a), R^(12b), R^(6a), R^(6b), R^(15a), R^(15b), R^(16a),and R^(16b) is hydrogen.

In some embodiments, the compound is a compound of Formula (I) and n is1, R²² is —CN, R⁵ is hydrogen, and R¹⁹ is selected from the groupconsisting of hydrogen, methyl, and ethyl.

In some embodiments, the compound is a compound of Formula (I) and n is1, R²² is —CN, R⁵ is hydrogen, and R¹⁹ is hydrogen.

Groups R^(1a) and R^(1b)

In some embodiments, each R^(1a) and R^(1b) is independently selectedfrom the group consisting of hydrogen, halogen, cyano, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₃₋₆carbocyclyl,substituted or unsubstituted 3- to 6-membered heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,—OR^(A1), —N(R^(A1))₂, —C(═O)R^(A1), —C(═O)OR^(A1), and—C(═O)N(R^(A1))₂, wherein each instance of R^(A1) is independentlyselected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₆alkyl, substituted or unsubstituted C₂₋₆alkenyl,substituted or unsubstituted C₂₋₆alkynyl, substituted or unsubstitutedC₃₋₆carbocyclyl, substituted or unsubstituted 3- to 6-memberedheterocyclyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl.

In some embodiments, each R^(1a) and R^(1b) is independently selectedfrom the group consisting of hydrogen, halogen, cyano, substituted orunsubstituted C₁₋₆ alkyl, and —OR^(A1) wherein R^(A1) is selected fromthe group consisting of hydrogen, substituted or unsubstituted C₁.6alkyl, substituted or unsubstituted C₃₋₆carbocyclyl, substituted orunsubstituted 3- to 6-membered heterocyclyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl.

In some embodiments, each R^(1a) and R^(1b) is independently selectedfrom the group consisting of hydrogen, substituted or unsubstituted C₁₋₆alkyl, and —OR^(A1), wherein R^(A1) is hydrogen or unsubstituted C₁₋₆alkyl.

In some embodiments, each of R^(1a) and R^(1b) is independently hydrogenor substituted or unsubstituted C₁₋₆ alkyl.

In some embodiments, R^(1a) and R^(1b) are both hydrogen.

Groups R^(2a) and R^(2b)

In some embodiments, each R^(2a) and R^(2b) is independently selectedfrom the group consisting of hydrogen, halogen, cyano, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₃₋₆ carbocyclyl,substituted or unsubstituted 3- to 6-membered heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,—OR^(A1), —N(R^(A1))₂, —C(═O)R^(A1), —C(═O)OR^(A1), and—C(═O)N(R^(A1))₂, wherein each instance of R^(A1) is independentlyselected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆alkynyl, substituted or unsubstitutedC₃₋₆ carbocyclyl, or substituted or unsubstituted 3- to 6-memberedheterocyclyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl.

In some embodiments, each R^(2a) and R^(2b) is independently selectedfrom the group consisting of hydrogen, halogen, cyano, substituted orunsubstituted C₁₋₆ alkyl, and —OR^(A1) wherein R^(A1) is selected fromthe group consisting of hydrogen, substituted or unsubstituted C₁₋₆alkyl, substituted or unsubstituted C₃₋₆ carbocyclyl, substituted orunsubstituted 3- to 6-membered heterocyclyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl.

In some embodiments, each R^(2a) and R^(2b) is independently selectedfrom the group consisting of hydrogen, substituted or unsubstituted C₁₋₆alkyl, and —OR^(A1), wherein R^(A1) is hydrogen or unsubstituted C₁₋₆alkyl.

In some embodiments, each R^(2a) and R^(2b) is independently selectedfrom the group consisting of hydrogen, methyl, ethyl, methoxymethyl, andmethoxy.

In some embodiments, R^(2a) and R^(2b) are both hydrogen.

Groups R^(4a) and R^(4b)

In some embodiments, each R^(4a) and R^(4b) is independently selectedfrom the group consisting of hydrogen, halogen, cyano, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₃₋₆ carbocyclyl,substituted or unsubstituted 3- to 6-membered heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,—OR^(A1), —N(R^(A1))₂, —C(═O)R^(A1), —C(═O)OR^(A1), and—C(═O)N(R^(A1))₂, wherein each instance of R^(A1) is independentlyselected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆ alkynyl, substituted or unsubstitutedC₃₋₆ carbocyclyl, or substituted or unsubstituted 3- to 6-memberedheterocyclyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl.

In some embodiments, each R^(4a) and R^(4b) is independently selectedfrom the group consisting of hydrogen, halogen, cyano, substituted orunsubstituted C₁₋₆ alkyl, and —OR^(A1) wherein R^(A1) is selected fromthe group consisting of from hydrogen, substituted or unsubstituted C₁₋₆alkyl, substituted or unsubstituted C₃₋₆ carbocyclyl, or substituted orunsubstituted 3- to 6-membered heterocyclyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl.

In some embodiments, each R^(4a) and R^(4b) is independently selectedfrom the group consisting of hydrogen, substituted or unsubstituted C₁₋₆alkyl, and —OR^(A1), wherein R^(A1) is hydrogen or unsubstituted C₁₋₆alkyl.

In some embodiments, each R^(4a) and R^(4b) is independently hydrogen orsubstituted or unsubstituted C₁₋₆ alkyl.

In some embodiments, R^(4a) and R^(4b) are both hydrogen.

Groups R^(7a) and R^(7b)

In some embodiments, each R^(7a) and R^(7b) is independently selectedfrom the group consisting of hydrogen, halogen, cyano, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₃₋₆ carbocyclyl,substituted or unsubstituted 3- to 6-membered heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,—OR^(A1), —N(R^(A1))₂, —C(═O)R^(A1), —C(═O)OR^(A1), and—C(═O)N(R^(A1))₂, wherein each instance of R^(A1) is independentlyselected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆ alkynyl, substituted or unsubstitutedC₃₋₆ carbocyclyl, or substituted or unsubstituted 3- to 6-memberedheterocyclyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl.

In some embodiments, each R^(7a) and R^(7b) is independently selectedfrom the group consisting of hydrogen, halogen, cyano, substituted orunsubstituted C₁₋₆ alkyl, and —OR^(A1) wherein R^(A1) is selected fromthe group consisting of from hydrogen, substituted or unsubstituted C₁₋₆alkyl, substituted or unsubstituted C₃₋₆ carbocyclyl, or substituted orunsubstituted 3- to 6-membered heterocyclyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl.

In some embodiments, each R^(7a) and R^(7b) is independently selectedfrom the group consisting of hydrogen, substituted or unsubstituted C₁₋₆alkyl, and —OR^(A1), wherein R^(A1) is hydrogen or unsubstituted C₁₋₆alkyl.

In some embodiments, each R^(7a) and R^(7b) is independently hydrogen orsubstituted or unsubstituted C₁₋₆ alkyl.

In some embodiments, R^(7a) and R^(7b) are both hydrogen.

Groups R^(11a) and R^(11b)

In some embodiments, each R^(11a) and R^(11b) is independently selectedfrom the group consisting of hydrogen, halogen, cyano, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₃₋₆ carbocyclyl,substituted or unsubstituted 3- to 6-membered heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,—OR^(A1), —N(R^(A1))₂, —C(═O)R^(A1), —C(═O)OR^(A1), and—C(═O)N(R^(A1))₂, wherein each instance of R^(A1) is independentlyselected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆ alkynyl, substituted or unsubstitutedC₃₋₆ carbocyclyl, or substituted or unsubstituted 3- to 6-memberedheterocyclyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl.

In some embodiments, each R^(11a) and R^(11b) is independently selectedfrom the group consisting of hydrogen, halogen, cyano, substituted orunsubstituted C₁₋₆ alkyl, and —OR^(A1) wherein R^(A1) is independentlyselected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₃₋₆ carbocyclyl,or substituted or unsubstituted 3- to 6-membered heterocyclyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

In some embodiments, each R^(11a) and R^(11b) is independently selectedfrom the group consisting of hydrogen, substituted or unsubstituted C₁₋₆alkyl, and —OR^(A1), wherein R^(A1) is hydrogen or unsubstituted C₁₋₆alkyl.

In some embodiments, each R^(11a) and R^(11b) is independently hydrogenor substituted or unsubstituted C₁₋₆ alkyl.

In some embodiments, R^(11a) and R^(11b) are both hydrogen.

Groups R^(12a) and R^(12b)

In some embodiments, each R^(12a) and R^(12b) is independently selectedfrom the group consisting of hydrogen, halogen, cyano, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₃₋₆ carbocyclyl,substituted or unsubstituted 3- to 6-membered heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,—OR^(A1), —N(R^(A1))₂, —C(═O)R^(A1), —C(═O)OR^(A1), and—C(═O)N(R^(A1))₂, wherein each instance of R^(A1) is independentlyselected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆ alkynyl, substituted or unsubstitutedC₃₋₆ carbocyclyl, or substituted or unsubstituted 3- to 6-memberedheterocyclyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl.

In some embodiments, each R^(12a) and R^(12b) is independently selectedfrom the group consisting of hydrogen, halogen, cyano, substituted orunsubstituted C₁₋₆ alkyl, and —OR^(A1) wherein R^(A1) is independentlyselected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₃₋₆ carbocyclyl,or substituted or unsubstituted 3- to 6-membered heterocyclyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

In some embodiments, each R^(12a) and R^(12b) is independently selectedfrom the group consisting of hydrogen, substituted or unsubstituted C₁₋₆alkyl, and —OR^(A1), wherein R^(A1) is hydrogen or unsubstituted C₁₋₆alkyl.

In some embodiments, each R^(12a) and R^(12b) is independently hydrogenor substituted or unsubstituted C₁₋₆ alkyl.

In some embodiments, R^(12a) and R^(12b) are both hydrogen.

Groups R^(6a) and R^(6b)

In some embodiments, each R^(6a) and R^(6b) is independently selectedfrom the group consisting of hydrogen, halogen, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆ alkenyl, andsubstituted or unsubstituted C₂₋₆ alkynyl.

In some embodiments, each R^(6a) and R^(6b) is independently hydrogen orsubstituted or unsubstituted C₁₋₆ alkyl.

In some embodiments, each R^(6a) and R^(6b) is independently hydrogen orunsubstituted C₁₋₆ alkyl.

In some embodiments, R^(6a) and R^(6b) are both hydrogen.

Groups R^(15a) and R^(15b)

In some embodiments, each R^(15a) and R^(15b) is independently selectedfrom the group consisting of hydrogen, halogen, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₃₋₆ carbocyclyl,and substituted or unsubstituted heteroaryl.

In some embodiments, each R^(15a) and R^(15b) is independently selectedfrom the group consisting of hydrogen, unsubstituted C₁₋₆ alkyl, andunsubstituted C₃₋₆ carbocyclyl.

In some embodiments, each R^(15a) and R^(15b) is independently selectedfrom the group consisting of hydrogen, methyl, and cyclopropyl.

In some embodiments, R^(15a) and R^(15b) are both hydrogen.

Groups R^(16a) and R^(16b)

In some embodiments, each R^(16a) and R^(16b) is independently selectedfrom the group consisting of hydrogen, halogen, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₃₋₆ carbocyclyl,and substituted or unsubstituted heteroaryl.

In some embodiments, each R^(16a) and R^(16b) is independently hydrogenor substituted or unsubstituted C₁₋₆ alkyl.

In some embodiments, each R^(16a) and R^(16b) is independently hydrogenor unsubstituted C₁₋₆ alkyl.

In some embodiments, R^(16a) and R^(16b) are both hydrogen.

Group R³

In some embodiments, R³ is selected from the group consisting ofsubstituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₂₋₆ alkenyl, and substituted or unsubstituted C₂₋₆ alkynyl.

In some embodiments, R³ is substituted or unsubstituted C₁-C₆alkyl.

In some embodiments, R³ is C₁₋₃ alkyl optionally substituted with C₁₋₃alkoxy.

In some embodiments, R³ is selected from the group consisting of methyl,ethyl, n-propyl, —CH₂OCH₃, and —CH₂OCH₂CH₃.

In some embodiments, R³ is methyl.

Group R¹⁹

In some embodiments, R¹⁹ is hydrogen or substituted or unsubstitutedC₁₋₆alkyl.

In some embodiments, R¹⁹ is hydrogen or unsubstituted C₁₋₃alkyl.

In some embodiments, R¹⁹ is selected from the group consisting ofhydrogen, methyl, and ethyl.

In some embodiments, R¹⁹ is hydrogen.

In some embodiments, R¹⁹ is unsubstituted C₁-C₃alkyl.

In some embodiments R¹⁹ is methyl or ethyl.

In some embodiments R¹⁹ is methyl.

In some embodiments, R¹⁹ is ethyl.

Group R^(X) and/or Group R^(Y)

In some embodiments, R^(X) is selected from the group consisting ofhalo, —CN, —OH, —OR^(Q1), and substituted or unsubstituted C₁₋₃alkyl.

In some embodiments, R^(X) is selected from the group consisting ofhalo, —CN, —OH, —OR^(Q1), and unsubstituted C₁₋₃alkyl.

In some embodiments, R^(X) is selected from the group consisting offluoro, —CN, —OH, —OCH₃, and methyl.

In some embodiments, R^(X) is —OH.

In some embodiments, R^(X) is fluoro.

In some embodiments, R^(X) is unsubstituted C₁-C₃alkylene-OR^(Q1)

In some embodiments, R^(Y) is halo or unsubstituted C₁₋₆alkyl.

In some embodiments, R^(Y) is halo or unsubstituted C₁₋₃alkyl.

In some embodiments, R is selected from the group consisting of methyl,ethyl, and n-propyl.

In some embodiments, R is methyl.

In some embodiments, R^(Y) is fluoro.

In some embodiments, R^(Y) and R^(X) join together with the interveningatoms to form a substituted or unsubstituted C₃₋₆carbocyclyl or asubstituted or unsubstituted 3- to 6-membered heterocyclyl.

In some embodiments R and R^(X) join together with the intervening atomsto form an unsubstituted C₃₋₆ carbocyclyl or an unsubstituted 3- to6-membered heterocyclyl.

In some embodiments, R^(Y) and R^(X) join together with the interveningatoms to form a substituted or unsubstituted 4-membered carbocyclyl.

In some embodiments, R^(Y) and R^(X) join together with the interveningatoms to form a substituted or unsubstituted 4-membered heterocyclyl.

In some embodiments, the 4-membered heterocyclic ring contains aheteroatom selected from N, O, and S.

In some embodiments, R^(Y) and R^(X) join together to form an oxetane.

Group R^(Q1)

In some embodiments, R^(Q1) is unsubstituted C₁₋₆alkyl.

In some embodiments, R^(Q1) is unsubstituted C₁₋₃alkyl.

In some embodiments, R^(Q1) is selected from the group consisting ofmethyl, ethyl, and n-propyl.

In some embodiments, R^(Q1) is methyl.

Group R²²

In some embodiments, each R²² is independently selected from the groupconsisting of halogen, —NO₂, —CN, —OR^(GA), —N(R^(GA))₂, —C(═O)R^(GA),—C(═O)OR^(GA), —N(R^(GA))C(═O)R^(GA), —SR^(GA), —S(═O) R^(GA),—S(═O)₂R^(GA), —S(═O)₂OR^(GA), —OS(═O)₂R^(GA), —S(═O)₂N(R^(GA))₂,substituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₃₋₆ carbocylyl, and substituted or unsubstituted 3- to 6-memberedheterocyclyl, wherein each instance of R^(GA) is independently selectedfrom the group consisting of hydrogen, substituted or unsubstituted C₁₋₆alkyl, substituted or unsubstituted C₃₋₆ carbocylyl, substituted orunsubstituted 3- to 6-membered heterocyclyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl.

In some embodiments, each R²² is independently selected from the groupconsisting of halogen, —CN, substituted or unsubstituted C₁₋₃ alkyl,substituted or unsubstituted 3- to 6-membered heterocyclyl, and—OR^(GA), wherein R^(GA) is hydrogen or substituted or unsubstitutedC₁₋₃ alkyl.

In some embodiments, R²² is —CN or C₁₋₃ alkyl optionally substitutedwith oxo.

In some embodiments, R²² is located at the 4-position of the pyrazolyl.In some embodiments, R²² is located at the 3-position of the pyrazolyl.In another embodiment, R²² is located at the 5-position of thepyrazolyl.

In some embodiments, R²² is —CN.

In another embodiment, R²² is —CN located at the 4-position of thepyrazolyl.

Integer n

In some embodiments n is 1, 2, or 3.

In some embodiments, n is 1 or 2.

In some embodiments n is 0 or 1.

In some embodiments n is 0. In some embodiments n is 1. In someembodiments n is 2. In some embodiments n is 3.

Group R⁵

In some embodiments, R⁵ is hydrogen.

In some embodiments, R⁵ is a hydrogen in the alpha or betaconfiguration.

In some embodiments, R⁵ is a hydrogen in the alpha configuration.

In some embodiments, R⁵ is a hydrogen in the beta configuration.

In some embodiments, the compound of Formula I is a compound of FormulaI-b1:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I is a compound of FormulaI-c3 or Formula I-c4:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I is a compound of FormulaI-d3 or Formula I-d4:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I is a compound of FormulaI-e5, Formula I-e6, Formula I-e7, or Formula I-e8:

or a pharmaceutically acceptable salt thereof.

In one embodiment, the compound of Formula I is a compound of FormulaI-Ib1:

or a pharmaceutically acceptable salt thereof,

-   -   wherein R²² is CN;    -   n is 1;    -   R¹⁹ is selected from the group consisting of hydrogen, ethyl,        and methyl;    -   R^(15a) and R^(15b) is independently selected from the group        consisting of hydrogen, methyl, and cyclopropyl;    -   R^(2a) and R^(2b) is each independently selected from the group        consisting of hydrogen, methyl, ethyl, methoxymethyl, and        methoxy;    -   R³ is selected from the group consisting of unsubstituted C₁₋₃        alkyl, —CH₂OCH₃, and —CH₂OCH₂CH₃; and    -   R^(X) and R^(Y) are as defined herein.

In one embodiment, the compound is a compound of Formula I-Ic1 orFormula I-Ic2:

or a pharmaceutically acceptable salt thereof,

-   -   wherein R²² is CN;    -   n is 1;    -   R¹⁹ is selected from the group consisting of hydrogen, ethyl,        and methyl;    -   R^(15a) and R^(15b) is independently selected from the group        consisting of hydrogen, methyl, and cyclopropyl;    -   R^(2a) and R^(2b) is each independently selected from the group        consisting of hydrogen, methyl, ethyl, methoxymethyl, and        methoxy;    -   R³ is selected from the group consisting of unsubstituted C₁₋₃        alkyl, —CH₂OCH₃, and —CH₂OCH₂CH₃; and    -   R^(X) and R^(Y) are as defined herein.

In one embodiment, the compound is a compound of Formula I-Id1 orFormula I-Id2:

or a pharmaceutically acceptable salt thereof,

-   -   wherein R²² is CN;    -   R¹⁹ is selected from the group consisting of hydrogen, ethyl,        and methyl;    -   R^(15a) and R^(15b) is independently selected from the group        consisting of hydrogen, methyl, and cyclopropyl;    -   R^(2a) and R^(2b) is each independently selected from the group        consisting of hydrogen, methyl, ethyl, methoxymethyl, and        methoxy;    -   R³ is selected from the group consisting of unsubstituted C₁₋₃        alkyl, —CH₂OCH₃, and —CH₂OCH₂CH₃; and    -   R^(X) and R^(Y) are as defined herein.

In one embodiment, the compound is a compound of Formula I-Ie1, FormulaI-Ie2, Formula I-Ie3, or Formula I-Ie4:

or a pharmaceutically acceptable salt thereof,

-   -   wherein R²² is CN;    -   R¹⁹ is selected from the group consisting of hydrogen, ethyl,        and methyl;    -   R^(15a) and R¹ is independently selected from the group        consisting of hydrogen, methyl, and cyclopropyl;    -   R^(2a) and R^(2b) is each independently selected from the group        consisting of hydrogen, methyl, ethyl, methoxymethyl, and        methoxy;    -   R³ is selected from the group consisting of unsubstituted C₁₋₃        alkyl, —CH₂OCH₃, and —CH₂OCH₂CH₃; and    -   R^(X) and R^(Y) are as defined herein.

In some embodiments, a pharmaceutical composition comprises a compounddescribed herein or pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient.

In some embodiments, a method of treating a CNS-related disorder in asubject in need thereof, comprises administering to the subject aneffective amount of a compound described herein or a pharmaceuticallyacceptable salt thereof. In some embodiments, the CNS-related disorderis a sleep disorder, a mood disorder, a schizophrenia spectrum disorder,a convulsive disorder, a disorder of memory and/or cognition, a movementdisorder, a personality disorder, autism spectrum disorder, pain,traumatic brain injury, a vascular disease, a substance abuse disorderand/or withdrawal syndrome, tinnitus, or status epilepticus. In someembodiments, the CNS-related disorder is depression. In someembodiments, the CNS-related disorder is postpartum depression. In someembodiments, the CNS-related disorder is major depressive disorder. Insome embodiments, the major depressive disorder is moderate majordepressive disorder. In some embodiments, the major depressive disorderis severe major depressive disorder.

In some embodiments, the compound is selected from the group consistingof the compounds identified in Table 1 below:

TABLE 1 Compound No. Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

58A

59A

60

61

indicates data missing or illegible when filed

In one aspect, provided herein is a pharmaceutically acceptable salt ofa compound described herein (e.g., a compound of Formula (I)).

In one aspect, provided herein is a pharmaceutical compositioncomprising a compound described herein (e.g., a compound of Formula (I))or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient. In certain embodiments, the compound of thepresent invention is provided in an effective amount in thepharmaceutical composition. In certain embodiments, the compound of thepresent invention is provided in a therapeutically effective amount.

Compounds of the present invention as described herein, act, in certainembodiments, as GABA modulators, e.g., effecting the GABA_(A) receptorin either a positive or negative manner. As modulators of theexcitability of the central nervous system (CNS), as mediated by theirability to modulate GABA_(A) receptor, such compounds are expected tohave CNS-activity.

Thus, in another aspect, provided are methods of treating a CNS-relateddisorder in a subject in need thereof, comprising administering to thesubject an effective amount of a compound of the present invention. Incertain embodiments, CNS-related disorder is a sleep disorder, a mooddisorder, a schizophrenia spectrum disorder, a convulsive disorder, adisorder of memory and/or cognition, a movement disorder, a personalitydisorder, autism spectrum disorder, pain, traumatic brain injury, avascular disease, a substance abuse disorder and/or withdrawal syndrome,tinnitus, or status epilepticus. In certain embodiments, the CNS-relateddisorder is depression. In certain embodiments, the CNS-related disorderis postpartum depression. In certain embodiments, the CNS-relateddisorder is major depressive disorder. In certain embodiments, the majordepressive disorder is moderate major depressive disorder. In certainembodiments, the major depressive disorder is severe major depressivedisorder. In certain embodiments, the compound is administered orally,subcutaneously, intravenously, or intramuscularly. In certainembodiments, the compound is administered orally. In certainembodiments, the compound is administered chronically. In certainembodiments, the compound is administered continuously, e.g., bycontinuous intravenous infusion.

Exemplary compounds of the invention may be synthesized from thefollowing known starting materials using methods known to one skilled inthe art or certain references, In one aspect, provided herein is apharmaceutically acceptable salt of a compound described herein (e.g., acompound of Formula (I)).

Alternative Embodiments

In an alternative embodiment, compounds described herein may alsocomprise one or more isotopic substitutions. For example, hydrogen maybe ²H (D or deuterium) or ³H (T or tritium); carbon may be, for example,¹³C or ¹⁴C; oxygen may be, for example, 180; nitrogen may be, forexample, ¹⁵N, and the like. In other embodiments, a particular isotope(e.g., ³H, ¹³C, ¹⁴C, ¹⁸O, or ¹⁵N) can represent at least 1%, at least5%, at least 10%, at least 15%, at least 20%, at least 25%, at least30%, at least 35%, at least 40%, at least 45%, at least 50%, at least60%, at least 65%, at least 70%, at least 75%, at least 80%, at least85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of thetotal isotopic abundance of an element that occupies a specific site ofthe compound.

Pharmaceutical Compositions

In one aspect, provided herein is a pharmaceutical compositioncomprising a compound described herein (e.g., a compound of Formula (I))or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient. In certain embodiments, the compound of thepresent invention is provided in an effective amount in thepharmaceutical composition. In certain embodiments, the compound of thepresent invention is provided in a therapeutically effective amount.

In certain embodiments, the pharmaceutical composition comprises aneffective amount of the active ingredient. In certain embodiments, thepharmaceutical composition comprises a therapeutically effective amountof the active ingredient.

The pharmaceutical compositions provided herein can be administered by avariety of routes including, but not limited to, oral (enteral)administration, parenteral (by injection) administration, rectaladministration, transdermal administration, intradermal administration,intrathecal administration, subcutaneous (SC) administration,intravenous (IV) administration, intramuscular (IM) administration, andintranasal administration.

Generally, the compounds provided herein are administered in aneffective amount. The amount of the compound actually administered willtypically be determined by a physician, in the light of the relevantcircumstances, including the condition to be treated, the chosen routeof administration, the actual compound administered, the age, weight,and response of the individual patient, the severity of the patient'ssymptoms, and the like.

When used to prevent the onset of a CNS-disorder, the compounds providedherein will be administered to a subject at risk for developing thecondition, typically on the advice and under the supervision of aphysician, at the dosage levels described above. Subjects at risk fordeveloping a particular condition generally include those that have afamily history of the condition, or those who have been identified bygenetic testing or screening to be particularly susceptible todeveloping the condition.

The pharmaceutical compositions provided herein can also be administeredchronically (“chronic administration”). Chronic administration refers toadministration of a compound or pharmaceutical composition thereof overan extended period of time, e.g., for example, over 3 months, 6 months,1 year, 2 years, 3 years, 5 years, etc, or may be continuedindefinitely, for example, for the rest of the subject's life. Incertain embodiments, the chronic administration is intended to provide aconstant level of the compound in the blood, e.g., within thetherapeutic window over the extended period of time.

The pharmaceutical compositions of the present invention may be furtherdelivered using a variety of dosing methods. For example, in certainembodiments, the pharmaceutical composition may be given as a bolus,e.g., in order to raise the concentration of the compound in the bloodto an effective level. The placement of the bolus dose depends on thesystemic levels of the active ingredient desired throughout the body,e.g., an intramuscular or subcutaneous bolus dose allows a slow releaseof the active ingredient, while a bolus delivered directly to the veins(e.g., through an IV drip) allows a much faster delivery which quicklyraises the concentration of the active ingredient in the blood to aneffective level. In other embodiments, the pharmaceutical compositionmay be administered as a continuous infusion, e.g., by IV drip, toprovide maintenance of a steady-state concentration of the activeingredient in the subject's body. Furthermore, in still yet otherembodiments, the pharmaceutical composition may be administered as firstas a bolus dose, followed by continuous infusion.

The compositions for oral administration can take the form of bulkliquid solutions or suspensions, or bulk powders. More commonly,however, the compositions are presented in unit dosage forms tofacilitate accurate dosing. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient. Typical unitdosage forms include prefilled, premeasured ampules or syringes of theliquid compositions or pills, tablets, capsules or the like in the caseof solid compositions. In such compositions, the compound is usually aminor component (from about 0.1 to about 50% by weight or preferablyfrom about 1 to about 40% by weight) with the remainder being variousvehicles or excipients and processing aids helpful for forming thedesired dosing form.

With oral dosing, one to five and especially two to four and typicallythree oral doses per day are representative regimens. Using these dosingpatterns, each dose provides from about 0.01 to about 20 mg/kg of thecompound provided herein, with preferred doses each providing from about0.1 to about 10 mg/kg, and especially about 1 to about 5 mg/kg.

Transdermal doses are generally selected to provide similar or lowerblood levels than are achieved using injection doses, generally in anamount ranging from about 0.01 to about 20% by weight, preferably fromabout 0.1 to about 20% by weight, preferably from about 0.1 to about 10%by weight, and more preferably from about 0.5 to about 15% by weight.

Injection dose levels range from about 0.1 mg/kg/hour to at least 20mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to96 hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kgor more may also be administered to achieve adequate steady statelevels. The maximum total dose is not expected to exceed about 5 g/dayfor a 40 to 80 kg human patient.

Liquid forms suitable for oral administration may include a suitableaqueous or nonaqueous vehicle with buffers, suspending and dispensingagents, colorants, flavors and the like. Solid forms may include, forexample, any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable excipients knownin the art. As before, the active compound in such compositions istypically a minor component, often being from about 0.05 to 10% byweight with the remainder being the injectable excipient and the like.

Transdermal compositions are typically formulated as a topical ointmentor cream containing the active ingredient(s). When formulated as anointment, the active ingredients will typically be combined with eithera paraffinic or a water-miscible ointment base. Alternatively, theactive ingredients may be formulated in a cream with, for example anoil-in-water cream base. Such transdermal formulations are well-known inthe art and generally include additional ingredients to enhance thedermal penetration of stability of the active ingredients orFormulation. All such known transdermal formulations and ingredients areincluded within the scope provided herein.

The compounds provided herein can also be administered by a transdermaldevice. Accordingly, transdermal administration can be accomplishedusing a patch either of the reservoir or porous membrane type, or of asolid matrix variety.

The above-described components for orally administrable, injectable ortopically administrable compositions are merely representative. Othermaterials as well as processing techniques and the like are set forth inPart 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, MackPublishing Company, Easton, Pa., which is incorporated herein byreference.

The compounds of the present invention can also be administered insustained release forms or from sustained release drug delivery systems.A description of representative sustained release materials can be foundin Remington's Pharmaceutical Sciences.

The present invention also relates to the pharmaceutically acceptableacid addition salt of a compound of the present invention. The acidwhich may be used to prepare the pharmaceutically acceptable salt isthat which forms a non-toxic acid addition salt, i.e., a salt containingpharmacologically acceptable anions such as the hydrochloride,hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate,acetate, lactate, citrate, tartrate, succinate, maleate, fumarate,benzoate, para-toluenesulfonate, and the like.

In another aspect, the invention provides a pharmaceutical compositioncomprising a compound of the present invention and a pharmaceuticallyacceptable excipient, e.g., a composition suitable for injection, suchas for intravenous (IV) administration.

Pharmaceutically acceptable excipients include any and all diluents orother liquid vehicles, dispersion or suspension aids, surface activeagents, isotonic agents, preservatives, lubricants and the like, assuited to the particular dosage form desired, e.g., injection. Generalconsiderations in the formulation and/or manufacture of pharmaceuticalcompositions agents can be found, for example, in Remington'sPharmaceutical Sciences, Sixteenth Edition, E. W. Martin (MackPublishing Co., Easton, Pa., 1980), and Remington: The Science andPractice of Pharmacy, 21^(st) Edition (Lippincott Williams & Wilkins,2005).

For example, injectable preparations, such as sterile injectable aqueoussuspensions, can be formulated according to the known art using suitabledispersing or wetting agents and suspending agents. Exemplary excipientsthat can be employed include, but are not limited to, water, sterilesaline or phosphate-buffered saline, or Ringer's solution.

In certain embodiments, the pharmaceutical composition further comprisesa cyclodextrin derivative. The most common cyclodextrins are α-, β- andγ- cyclodextrins consisting of 6, 7 and 8 α-1,4-linked glucose units,respectively, optionally comprising one or more substituents on thelinked sugar moieties, which include, but are not limited to,substituted or unsubstituted methylated, hydroxyalkylated, acylated, andsulfoalkylether substitution. In certain embodiments, the cyclodextrinis a sulfoalkyl ether O-cyclodextrin, e.g., for example, sulfobutylether O-cyclodextrin, also known as CAPTISOL®. See, e.g., U.S. Pat. No.5,376,645. In certain embodiments, the composition compriseshexapropyl-p-cyclodextrin. In a more particular embodiment, thecomposition comprises hexapropyl-p-cyclodextrin (10-50% in water).

The injectable composition can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

Generally, the compounds provided herein are administered in aneffective amount. The amount of the compound actually administered willtypically be determined by a physician, in the light of the relevantcircumstances, including the condition to be treated, the chosen routeof administration, the actual compound administered, the age, weight,response of the individual patient, the severity of the patient'ssymptoms, and the like.

The compositions are presented in unit dosage forms to facilitateaccurate dosing. The term “unit dosage forms” refers to physicallydiscrete units suitable as unitary dosages for human subjects and othermammals, each unit containing a predetermined quantity of activematerial calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient. Typical unitdosage forms include pre-filled, pre-measured ampules or syringes of theliquid compositions. In such compositions, the compound is usually aminor component (from about 0.1% to about 50% by weight or preferablyfrom about 1% to about 40% by weight) with the remainder being variousvehicles or carriers and processing aids helpful for forming the desireddosing form.

The compounds provided herein can be administered as the sole activeagent, or they can be administered in combination with other activeagents. In one aspect, the present invention provides a combination of acompound of the present invention and another pharmacologically activeagent. Administration in combination can proceed by any techniqueapparent to those of skill in the art including, for example, separate,sequential, concurrent, and alternating administration.

Although the descriptions of pharmaceutical compositions provided hereinare principally directed to pharmaceutical compositions which aresuitable for administration to humans, it will be understood by theskilled artisan that such compositions are generally suitable foradministration to animals of all sorts. Modification of pharmaceuticalcompositions suitable for administration to humans in order to renderthe compositions suitable for administration to various animals is wellunderstood, and the ordinarily skilled veterinary pharmacologist candesign and/or perform such modification with ordinary experimentation.General considerations in the formulation and/or manufacture ofpharmaceutical compositions can be found, for example, in Remington: TheScience and Practice of Pharmacy 21^(st) ed., Lippincott Williams &Wilkins, 2005.

In one aspect, provided is a kit comprising a composition (e.g., a solidcomposition) comprising a compound of Formula (I).

Combination Therapy

A compound or composition described herein (e.g., a compound of FormulaI, or a pharmaceutical salt thereof, or a composition comprising acompound of Formula I, or a pharmaceutically acceptable salt thereof)may be administered in combination with an additional agent or therapy.A subject to be administered a compound disclosed herein may have adisease, disorder, or condition, or a symptom thereof, that wouldbenefit from treatment with another agent or therapy. Combinationtherapy may be achieved by administering two or more agents, each ofwhich is formulated and administered separately, or by administering twoor more agents in a single formulation. In some embodiments, the two ormore agents in the combination therapy can be administeredsimultaneously. In other embodiments, the two or more agents in thecombination therapy are administered separately. For example,administration of a first agent (or combination of agents) can precedeadministration of a second agent (or combination of agents) by minutes,hours, days, or weeks. Thus, the two or more agents can be administeredwithin minutes of each other or within 1, 2, 3, 6, 9, 12, 15, 18, or 24hours of each other or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 daysof each other or within 2, 3, 4, 5, 6, 7, 8, 9, or weeks of each other.In some cases even longer intervals are possible. While in many cases itis desirable that the two or more agents used in a combination therapybe present in within the patient's body at the same time, this need notbe so.

Combination therapy can also include two or more administrations of oneor more of the agents used in the combination using different sequencingof the component agents. For example, if agent X and agent Y are used ina combination, one could administer them sequentially in any combinationone or more times, e.g., in the order X—Y—X, X-X—Y, Y—X—Y, Y—Y—X,X-X—Y—Y, etc. Exemplary additional agents are described below.

Selective Serotonin Reuptake Inhibitor (SSRI)

In some embodiments, the compound or composition described herein (e.g.,a compound of Formula I, or a pharmaceutical salt thereof, or acomposition comprising a compound of Formula I, or a pharmaceuticallyacceptable salt thereof) is administered in combination with an SSRI(s).SSRIs include antidepressants that increase the level of serotonin inthe brain. Exemplary SSRIs include, but are not limited to, Citalopram(Celexa), Escitalopram (Lexapro), Fluoxetine (Prozac), Fluvoxamine(Luvox), Paroxetine (Paxil), and Sertraline (Zoloft).

Norepinephrine Reuptake Inhibitor (NERI)

In some embodiments, the compound or composition described herein (e.g.,a compound of Formula I, or a pharmaceutical salt thereof, or acomposition comprising a compound of Formula I, or a pharmaceuticallyacceptable salt thereof) is administered in combination with an NERI(s).Exemplary NERIs include, but are not limited to, Atomoxetine(Strattera), Reboxetine (Edronax, Vestra), Bupropion (Wellbutrin,Zyban), Duloxetine, Desipramine (Norpramin), Amedalin (UK-3540-1),Daledalin (UK-3557-15), Edivoxetine (LY-2216684), Esreboxetine,Lortalamine (LM−1404), Nisoxetine (LY-94,939), Talopram (tasulopram) (Lu3-010), Talsupram (Lu 5-005), Tandamine (AY-23,946), and Viloxazine(Vivalan).

Antipsychotics

In some embodiments, the compound or composition described herein (e.g.,a compound of Formula I, or a pharmaceutical salt thereof, or acomposition comprising a compound of Formula I, or a pharmaceuticallyacceptable salt thereof) is administered in combination with anantipsychotic agent(s). Antipsychotics include D2 antagonists, loweringdopaminergic neurotransmission in the dopamine pathways. Exemplaryantipsychotics include, but are not limited to, Asenapine (Saphris),Aripiprazole (Abilify), Cariprazine (Vrayar), Clozapine (Clozaril),Droperidol, Fluperlapine, Mesoridazine, Quetiapine Hemifumarate,Raclopride, Spiperone, Sulpiride, Trimethobenzamide hydrochloride,Trifluoperazine Dihydrochloride, lurasidone (Latuda), Olanzapine(Zyprexa), Quetiapine (Seroquel), Zotepine, Risperidone (Risperdal),Ziprasidone (Geodon), Mesotidazine, Chlorpromazine hydrochloride, andHaloperidol (Haldol).

Cannabinoids

In some embodiments, the compound or composition described herein (e.g.,a compound of Formula I, or a pharmaceutical salt thereof, or acomposition comprising a compound of Formula I, or a pharmaceuticallyacceptable salt thereof) is administered in combination with acannabinoid(s). Exemplary cannabinoids include, but are not limited to,Cannabidiol (Epidiolex), Tetrahydrocannabinolic Acid,Tetrahydrocannabinol, Cannabidolic Acid, Cannabinol, Cannabigerol,Cannabichromene, Tetrahydrocannabivarin, and Cannabidivarin.

NMDA Receptor Antagonists

In some embodiments, the compound or composition described herein (e.g.,a compound of Formula I, or a pharmaceutical salt thereof, or acomposition comprising a compound of Formula I, or a pharmaceuticallyacceptable salt thereof) is administered in combination with an NMDAreceptor antagonist(s). NMDA receptor antagonists are a class of drugsthat inhibit the action of the N-methyl-d-aspartate receptor. ExemplaryNMDA antagonists include, but are not limited to, Ketamine, Esketamine,Ketobemidone, Ifendopril, 5,7-Dichlorokynurenic Acid, Licostinel,Memantine, Gavestinel, Phencyclidine, Dextromethorphan, Remacemide,Selfotel, Tiletamine, Dextropropoxyphene, Aptiganel, Dexanabinol, andAmantadine. NMDA receptor antagonists also include opioids such asMethadone, Dextropropoxyphene, Pethidine, Levorphanol, Tramadol,Neramexane, and Ketobemidone.

GABA Receptor Agonists

In some embodiments, the compound or composition described herein (e.g.,a compound of Formula I, or a pharmaceutical salt thereof, or acomposition comprising a compound of Formula I, or a pharmaceuticallyacceptable salt thereof) is administered in combination with GABAreceptor agaonist(s). GABA receptor agonist are a class of drugs thatare agonists for one or more of the GABA receptors. Exemplary GABAreceptor agonists include, but are not limited to, Clobazam, Topiramate,Muscimol, Progabide, Riluzole, Baclofen, Gabapentin, Vigabatrin,Valproic Acid, Tiagabine, Lamotrigine, Pregabalin, Phenyloin,Carbamazepine, Thiopental, Thiamylal, Pentobarbital, Secobarbital,Hexobarbital, Butobarbital, Amobarbital, Barbital, Mephobarbital,Phenobarbital, Primidone, Midazolam, Triazolam, Lometazepam, Flutazolam,Nitrazepam, Fluritrazepam, Nimetazepam, Diazepam, Medazepam, Oxazolam,Prazeam, Tofisopam, Rilmazafonoe, Lorazepam, Temazepam, Oxazepam,Fluidazepam, Chlordizaepoxide, Cloxazolam, Flutoprazepam, Alprazolam,Estazolam, Bromazepam, Flurazepam, Clorazepate Potassium, Haloxazolam,Ethyl Loflazepate, Qazepam, Clonazepam, Mexazolam, Etizolam, Brotizolam,Clotizaepam, Propofol, Fospropofol, Zolpidem, Zopiclone, Exzopiclone,Muscimol, TFQP/gaboxadol, Isoguvacine, Kojic amine, GABA, Homotaurine,Homohypotaurine, Trans-aminocyclopentane-3-carboxylic acid,Trans-amino-4-crotonic acid, b-guanidinopropionic acid, homo-b-proline,Isonipecotic acid, 3-((aminoiminomethyl)thio)-2-propenoic acid (ZAP A),Imidazoleacetic acid, and Piperidine-4-sulfonic acid (P4S).

Cholinesterase Inhibitors

In some embodiments, the compound or composition described herein (e.g.,a compound of Formula I, or a pharmaceutical salt thereof, or acomposition comprising a compound of Formula I, or a pharmaceuticallyacceptable salt thereof) is administered in combination with acholinesterase inhibitor(s). In general, cholinergics are compoundswhich mimic the action of acetylcholine and/or butyrylcholine.Cholinesterase inhibitors are a class of drugs that prevent thebreakdown of acetylcholine. Exemplary cholinesterase inhibitors include,but are not limited to, Donepizil (Aricept), Tacrine (Cognex),Rivastigmine (Exelon, Exelon Patch), Galantamine (Razadyne, Reminyl),Memantine/Donepezil (Namzaric), Ambenonium (Mytelase), Neostigmine(Bloxiverz), Pyridostigmine (Mestinon Timespan, Regonol), andGalantamine (Razadyne).

The present disclosure also contemplates, among other thingsadministration of a compound or pharmaceutical composition describedherein (e.g., a compound of Formula I, or a pharmaceutical salt thereof,or a composition comprising a compound of Formula I, or apharmaceutically acceptable salt thereof) to a subject has beenpreviously administered an agent selected from the group consisting of abronchial muscle/airway relaxant, an antiviral, oxygen, an antibody, andan antibacterial. In some embodiments an additional agent isadministered to a subject prior to administration of a compound orpharmaceutical composition described herein (e.g., a compound of FormulaI, or a pharmaceutical salt thereof, or a composition comprising acompound of Formula I, or a pharmaceutically acceptable salt thereof)and an additional agent is selected from the group consisting of abronchial muscle/airway relaxant, an antiviral, oxygen, an antibody, andan antibacterial. In some embodiments, a compound or pharmaceuticalcomposition described herein (e.g., a compound of Formula I, or apharmaceutical salt thereof, or a composition comprising a compound ofFormula I, or a pharmaceutically acceptable salt thereof) isco-administered with to a subject with an agent selected from abronchial muscle/airway relaxant, an antiviral, oxygen, and anantibacterial.

Methods of Use and Treatment

In an aspect, compounds described herein, e.g., compounds of Formula(I), are envisioned to be useful as therapeutic agents for treating aCNS-related disorder (e.g., sleep disorder, a mood disorder such asdepression, a schizophrenia spectrum disorder, a convulsive disorder,epileptogenesis, a disorder of memory and/or cognition, a movementdisorder, a personality disorder, autism spectrum disorder, pain,traumatic brain injury, a vascular disease, a substance abuse disorderand/or withdrawal syndrome, or tinnitus) in a subject in need (e.g., asubject with Rett syndrome, Fragile X syndrome, or Angelman syndrome).Exemplary CNS conditions related to GABA-modulation include, but are notlimited to, sleep disorders [e.g., insomnia], mood disorders [e.g.,depression (e.g., major depressive disorder (MDD)), dysthymic disorder(e.g., mild depression), bipolar disorder (e.g., I and/or II), anxietydisorders (e.g., generalized anxiety disorder (GAD), social anxietydisorder), stress, post-traumatic stress disorder (PTSD), compulsivedisorders (e.g., obsessive compulsive disorder (OCD))], schizophreniaspectrum disorders [e.g., schizophrenia, schizoaffective disorder],convulsive disorders [e.g., epilepsy (e.g., status epilepticus (SE)),seizures], disorders of memory and/or cognition [e.g., attentiondisorders (e.g., attention deficit hyperactivity disorder (ADHD)),dementia (e.g., Alzheimer's type dementia, Lewis body type dementia,vascular type dementia], movement disorders [e.g., Huntington's disease,Parkinson's disease], personality disorders [e.g., anti-socialpersonality disorder, obsessive compulsive personality disorder], autismspectrum disorders (ASD) [e.g., autism, monogenetic causes of autismsuch as synaptophathy's, e.g., Rett syndrome, Fragile X syndrome,Angelman syndrome], pain [e.g., neuropathic pain, injury related painsyndromes, acute pain, chronic pain], traumatic brain injury (TBI),vascular diseases [e.g., stroke, ischemia, vascular malformations],substance abuse disorders and/or withdrawal syndromes [e.g., addition toopiates, cocaine, and/or alcohol], and tinnitus.

In certain embodiments, CNS-related disorder is a sleep disorder, a mooddisorder, a schizophrenia spectrum disorder, a convulsive disorder, adisorder of memory and/or cognition, a movement disorder, a personalitydisorder, autism spectrum disorder, pain, traumatic brain injury, avascular disease, a substance abuse disorder and/or withdrawal syndrome,tinnitus, or status epilepticus. In certain embodiments, the CNS-relateddisorder is depression. In certain embodiments, the CNS-related disorderis postpartum depression. In certain embodiments, the CNS-relateddisorder is major depressive disorder. In certain embodiments, the majordepressive disorder is moderate major depressive disorder. In certainembodiments, the major depressive disorder is severe major depressivedisorder.

In an aspect, provided is a method of alleviating or preventing seizureactivity in a subject, comprising administering to the subject in needof such treatment an effective amount of a compound of the presentinvention. In some embodiments, the method alleviates or preventsepileptogenesis.

In yet another aspect, provided is a combination of a compound of thepresent invention and another pharmacologically active agent. Thecompounds provided herein can be administered as the sole active agentor they can be administered in combination with other agents.Administration in combination can proceed by any technique apparent tothose of skill in the art including, for example, separate, sequential,concurrent and alternating administration.

In another aspect, provided is a method of treating or preventing brainexcitability in a subject susceptible to or afflicted with a conditionassociated with brain excitability, comprising administering to thesubject an effective amount of a compound of the present invention tothe subject.

In yet another aspect, provided is a method of treating or preventingstress or anxiety in a subject, comprising administering to the subjectin need of such treatment an effective amount of a compound of thepresent invention, or a composition thereof.

In yet another aspect, provided is a method of alleviating or preventinginsomnia in a subject, comprising administering to the subject in needof such treatment an effective amount of a compound of the presentinvention, or a composition thereof.

In yet another aspect, provided is a method of inducing sleep andmaintaining substantially the level of REM sleep that is found in normalsleep, wherein substantial rebound insomnia is not induced, comprisingadministering an effective amount of a compound of the presentinvention.

In yet another aspect, provided is a method of alleviating or preventingpremenstrual syndrome (PMS) or postnatal depression (PND) in a subject,comprising administering to the subject in need of such treatment aneffective amount of a compound of the present invention.

In yet another aspect, provided is a method of treating or preventingmood disorders in a subject, comprising administering to the subject inneed of such treatment an effective amount of a compound of the presentinvention. In certain embodiments the mood disorder is depression.

In yet another aspect, provided is a method of cognition enhancement ortreating memory disorder by administering to the subject atherapeutically effective amount of a compound of the present invention.In certain embodiments, the disorder is Alzheimer's disease. In certainembodiments, the disorder is Rett syndrome.

In yet another aspect, provided is a method of treating attentiondisorders by administering to the subject a therapeutically effectiveamount of a compound of the present invention. In certain embodiments,the attention disorder is ADHD.

Inflammation of the central nervous system (CNS) (neuroinflammation) isrecognized to be a feature of all neurological disorders. Majorinflammatory neurological disorders include multiple sclerosis(characterized by an immune-mediated response against myelin proteins),and meningoencephalitis (where infectious agents triggered theinflammatory response). Additional scientific evidence suggests apotential role of inflammatory mechanisms in other neurologicalconditions such as Alzheimer's disease, Parkinson's disease, Huntington'disease, amyotrophic lateral sclerosis, stroke and traumatic braininjuries. In one embodiment, the compounds of the present invention areuseful in treating neuroinflammation. In another embodiment, thecompounds of the present invention are useful in treating inflammationin neurological conditions, including Alzheimer's disease, Parkinson'sdisease, Huntington's disease, amyotrophic lateral sclerosis, stroke,and traumatic brain injuries.

In certain embodiments, the compound is administered to the subjectchronically. In certain embodiments, the compound is administered to thesubject orally, subcutaneously, intramuscularly, or intravenously.

Neuroendocrine Disorders and Dysfunction

Provided herein are methods that can be used for treating neuroendocrinedisorders and dysfunction. As used herein, “neuroendocrine disorder” or“neuroendocrine dysfunction” refers to a variety of conditions caused byimbalances in the body's hormone production directly related to thebrain. Neuroendocrine disorders involve interactions between the nervoussystem and the endocrine system. Because the hypothalamus and thepituitary gland are two areas of the brain that regulate the productionof hormones, damage to the hypothalamus or pituitary gland, e.g., bytraumatic brain injury, may impact the production of hormones and otherneuroendocrine functions of the brain. In some embodiments, theneuroendocrine disorder or dysfunction is associated with a women'shealth disorder or condition (e.g., a women's health disorder orcondition described herein). In some embodiments, the neuroendocrinedisorder or dysfunction is associated with a women's health disorder orcondition is polycystic ovary syndrome.

Symptoms of neuroendocrine disorder include, but are not limited to,behavioral, emotional, and sleep-related symptoms, symptoms related toreproductive function, and somatic symptoms; including but not limitedto fatigue, poor memory, anxiety, depression, weight gain or loss,emotional lability, lack of concentration, attention difficulties, lossof lipido, infertility, amenorrhea, loss of muscle mass, increased bellybody fat, low blood pressure, reduced heart rate, hair loss, anemia,constipation, cold intolerance, and dry skin.

Neurodegenerative Diseases and Disorders

The methods described herein can be used for treating neurodegenerativediseases and disorders. The term “neurodegenerative disease” includesdiseases and disorders that are associated with the progressive loss ofstructure or function of neurons, or death of neurons. Neurodegenerativediseases and disorders include, but are not limited to, Alzheimer'sdisease (including the associated symptoms of mild, moderate, or severecognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic andischemic injuries; ataxia and convulsion (including for the treatmentand prevention and prevention of seizures that are caused byschizoaffective disorder or by drugs used to treat schizophrenia);benign forgetfulness; brain edema; cerebellar ataxia including McLeodneuroacanthocytosis syndrome (MLS); closed head injury; coma; contusiveinjuries (e.g., spinal cord injury and head injury); dementias includingmulti-infarct dementia and senile dementia; disturbances ofconsciousness; Down syndrome; drug-induced or medication-inducedParkinsonism (such as neuroleptic-induced acute akathisia, acutedystonia, Parkinsonism, or tardive dyskinesia, neuroleptic malignantsyndrome, or medication-induced postural tremor); epilepsy; fragile Xsyndrome; Gilles de la Tourette's syndrome; head trauma; hearingimpairment and loss; Huntington's disease; Lennox syndrome;levodopa-induced dyskinesia; mental retardation; movement disordersincluding akinesias and akinetic (rigid) syndromes (including basalganglia calcification, corticobasal degeneration, multiple systematrophy, Parkinsonism-ALS dementia complex, Parkinson's disease,postencephalitic parkinsonism, and progressively supranuclear palsy);muscular spasms and disorders associated with muscular spasticity orweakness including chorea (such as benign hereditary chorea,drug-induced chorea, hemiballism, Huntington's disease,neuroacanthocytosis, Sydenham's chorea, and symptomatic chorea),dyskinesia (including tics such as complex tics, simple tics, andsymptomatic tics), myoclonus (including generalized myoclonus and focalcyloclonus), tremor (such as rest tremor, postural tremor, and intentiontremor) and dystonia (including axial dystonia, dystonic writer's cramp,hemiplegic dystonia, paroxysmal dystonia, and focal dystonia such asblepharospasm, oromandibular dystonia, and spasmodic dysphonia andtorticollis); neuronal damage including ocular damage, retinopathy ormacular degeneration of the eye; neurotoxic injury which followscerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebralischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia,perinatal asphyxia and cardiac arrest; Parkinson's disease; seizure;status epilecticus; stroke; tinnitus; tubular sclerosis, and viralinfection induced neurodegeneration (e.g., caused by acquiredimmunodeficiency syndrome (AIDS) and encephalopathies).Neurodegenerative diseases also include, but are not limited to,neurotoxic injury which follows cerebral stroke, thromboembolic stroke,hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia,amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest. Methodsof treating or preventing a neurodegenerative disease also includetreating or preventing loss of neuronal function characteristic ofneurodegenerative disorder.

Mood Disorders

Also provided herein are methods for treating a mood disorder, forexample clinical depression, postnatal depression or postpartumdepression, perinatal depression, atypical depression, melancholicdepression, psychotic major depression, cataonic depression, seasonalaffective disorder, dysthymia, double depression, depressive personalitydisorder, recurrent brief depression, minor depressive disorder, bipolardisorder or manic depressive disorder, depression caused by chronicmedical conditions, treatment-resistant depression, refractorydepression, suicidality, suicidal ideation, or suicidal behavior. Insome embodiments, the method described herein provides therapeuticeffect to a subject suffering from depression (e.g., moderate or severedepression). In some embodiments, the mood disorder is associated with adisease or disorder described herein (e.g., neuroendocrine diseases anddisorders, neurodegenerative diseases and disorders (e.g., epilepsy),movement disorders, tremor (e.g., Parkinson's Disease), women's healthdisorders or conditions).

Clinical depression is also known as major depression, major depressivedisorder (MDD), severe depression, unipolar depression, unipolardisorder, and recurrent depression, and refers to a mental disordercharacterized by pervasive and persistent low mood that is accompaniedby low self-esteem and loss of interest or pleasure in normallyenjoyable activities. Some people with clinical depression have troublesleeping, lose weight, and generally feel agitated and irritable.Clinical depression affects how an individual feels, thinks, and behavesand may lead to a variety of emotional and physical problems.Individuals with clinical depression may have trouble doing day-to-dayactivities and make an individual feel as if life is not worth living.

Peripartum depression refers to depression in pregnancy. Symptomsinclude irritability, crying, feeling restless, trouble sleeping,extreme exhaustion (emotional and/or physical), changes in appetite,difficulty focusing, increased anxiety and/or worry, disconnectedfeeling from baby and/or fetus, and losing interest in formerlypleasurable activities.

Postnatal depression (PND) is also referred to as postpartum depression(PPD), and refers to a type of clinical depression that affects womenafter childbirth. Symptoms can include sadness, fatigue, changes insleeping and eating habits, reduced sexual desire, crying episodes,anxiety, and irritability. In some embodiments, the PND is atreatment-resistant depression (e.g., a treatment-resistant depressionas described herein). In some embodiments, the PND is refractorydepression (e.g., a refractory depression as described herein).

In some embodiments, a subject having PND also experienced depression,or a symptom of depression during pregnancy. This depression is referredto herein as) perinatal depression. In an embodiment, a subjectexperiencing perinatal depression is at increased risk of experiencingPND.

Atypical depression (AD) is characterized by mood reactivity (e.g.,paradoxical anhedonia) and positivity, significant weight gain orincreased appetite. Patients suffering from AD also may have excessivesleep or somnolence (hypersomnia), a sensation of limb heaviness, andsignificant social impairment as a consequence of hypersensitivity toperceived interpersonal rejection.

Melancholic depression is characterized by loss of pleasure (anhedonia)in most or all activities, failures to react to pleasurable stimuli,depressed mood more pronounced than that of grief or loss, excessiveweight loss, or excessive guilt.

Psychotic major depression (PMD) or psychotic depression refers to amajor depressive episode, in particular of melancholic nature, where theindividual experiences psychotic symptoms such as delusions andhallucinations.

Catatonic depression refers to major depression involving disturbancesof motor behavior and other symptoms. An individual may become mute andstuporose, and either is immobile or exhibits purposeless or bizarremovements.

Seasonal affective disorder (SAD) refers to a type of seasonaldepression wherein an individual has seasonal patterns of depressiveepisodes coming on in the fall or winter.

Dysthymia refers to a condition related to unipolar depression, wherethe same physical and cognitive problems are evident. They are not assevere and tend to last longer (e.g., at least 2 years).

Double depression refers to fairly depressed mood (dysthymia) that lastsfor at least 2 years and is punctuated by periods of major depression.

Depressive Personality Disorder (DPD) refers to a personality disorderwith depressive features.

Recurrent Brief Depression (RBD) refers to a condition in whichindividuals have depressive episodes about once per month, each episodelasting 2 weeks or less and typically less than 2-3 days.

Minor depressive disorder or minor depression refers to a depression inwhich at least 2 symptoms are present for 2 weeks.

Bipolar disorder or manic depressive disorder causes extreme mood swingsthat include emotional highs (mania or hypomania) and lows (depression).During periods of mania the individual may feel or act abnormally happy,energetic, or irritable. They often make poorly thought out decisionswith little regard to the consequences. The need for sleep is usuallyreduced. During periods of depression there may be crying, poor eyecontact with others, and a negative outlook on life. The risk of suicideamong those with the disorder is high at greater than 6% over 20 years,while self-harm occurs in 30-40%. Other mental health issues such asanxiety disorder and substance use disorder are commonly associated withbipolar disorder.

Depression caused by chronic medical conditions refers to depressioncaused by chronic medical conditions such as cancer or chronic pain,chemotherapy, chronic stress.

Treatment-resistant depression refers to a condition where theindividuals have been treated for depression, but the symptoms do notimprove. For example, antidepressants or physchological counseling(psychotherapy) do not ease depression symptoms for individuals withtreatment-resistant depression. In some cases, individuals withtreatment-resistant depression improve symptoms, but come back.Refractory depression occurs in patients suffering from depression whoare resistant to standard pharmacological treatments, includingtricyclic antidepressants, MAOIs, SSRIs, and double and triple uptakeinhibitors and/or anxiolytic drugs, as well as non-pharmacologicaltreatments (e.g., psychotherapy, electroconvulsive therapy, vagus nervestimulation and/or transcranial magnetic stimulation).

Post-surgical depression refers to feelings of depression that follow asurgical procedure (e.g., as a result of having to confront one'smortality). For example, individuals may feel sadness or empty moodpersistently, a loss of pleasure or interest in hobbies and activitiesnormally enjoyed, or a persistent felling of worthlessness orhopelessness.

Mood disorder associated with conditions or disorders of women's healthrefers to mood disorders (e.g., depression) associated with (e.g.,resulting from) a condition or disorder of women's health (e.g., asdescribed herein).

Suicidality, suicidal ideation, suicidal behavior refers to the tendencyof an individual to commit suicide. Suicidal ideation concerns thoughtsabout or an unusual preoccupation with suicide. The range of suicidalideation varies greatly, from e.g., fleeting thoughts to extensivethoughts, detailed planning, role playing, incomplete attempts. Symptomsinclude talking about suicide, getting the means to commit suicide,withdrawing from social contact, being preoccupied with death, feelingtrapped or hopeless about a situation, increasing use of alcohol ordrugs, doing risky or self-destructive things, saying goodbye to peopleas if they won't be seen again.

Symptoms of depression include persistent anxious or sad feelings,feelings of helplessness, hopelessness, pessimism, worthlessness, lowenergy, restlessness, difficulty sleeping, sleeplessness, irritability,fatigue, motor challenges, loss of interest in pleasurable activities orhobbies, loss of concentration, loss of energy, poor self-esteem,absence of positive thoughts or plans, excessive sleeping, overeating,appetite loss, insomnia, self-harm, thoughts of suicide, and suicideattempts. The presence, severity, frequency, and duration of symptomsmay vary on a case to case basis. Symptoms of depression, and relief ofthe same, may be ascertained by a physician or psychologist (e.g., by amental state examination).

In some embodiments, the method comprises monitoring a subject with aknown depression scale, e.g., the Hamilton Depression (HAM-D) scale, theClinical Global Impression-Improvement Scale (CGI), and theMontgomery-Åsberg Depression Rating Scale (MADRS). In some embodiments,a therapeutic effect can be determined by reduction in HamiltonDepression (HAM-D) total score exhibited by the subject. Reduction inthe HAM-D total score can happen within 4, 3, 2, or 1 days; or 96, 84,72, 60, 48, 24, 20, 16, 12, 10, 8 hours or less. The therapeutic effectcan be assessed across a specified treatment period. For example, thetherapeutic effect can be determined by a decrease from baseline inHAM-D total score after administering a compound described herein, e.g.,a compound of Formula (I) (e.g., 12, 24, or 48 hours afteradministration; or 24, 48, 72, or 96 hours or more; or 1 day, 2 days, 14days, 21 days, or 28 days; or 1 week, 2 weeks, 3 weeks, or 4 weeks; or 1month, 2 months, 6 months, or 10 months; or 1 year, 2 years, or forlife).

In some embodiments, the subject has a mild depressive disorder, e.g.,mild major depressive disorder. In some embodiments, the subject has amoderate depressive disorder, e.g., moderate major depressive disorder.In some embodiments, the subject has a severe depressive disorder, e.g.,severe major depressive disorder. In some embodiments, the subject has avery severe depressive disorder, e.g., very severe major depressivedisorder. In some embodiments, the baseline HAM-D total score of thesubject (i.e., prior to treatment with a compound described herein,e.g., a compound of Formula (I)) is at least 24. In some embodiments,the baseline HAM-D total score of the subject is at least 18. In someembodiments, the baseline HAM-D total score of the subject is betweenand including 14 and 18. In some embodiments, the baseline HAM-D totalscore of the subject is between and including 19 and 22. In someembodiments, the HAM-D total score of the subject before treatment witha compound described herein, e.g., a compound of Formula (I), is greaterthan or equal to 23. In some embodiments, the baseline score is at least10, 15, or 20. In some embodiments, the HAM-D total score of the subjectafter treatment with a compound described herein, e.g., a compound ofFormula (I), is about 0 to 10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to4, 0 to 3, 0 to 2, or 1.8). In some embodiments, the HAM-D total scoreafter treatment with a compound described herein, e.g., a compound ofFormula (I), is less than 10, 7, 5, or 3. In some embodiments, thedecrease in HAM-D total score is from a baseline score of about 20 to 30(e.g., 22 to 28, 23 to 27, 24 to 27, 25 to 27, 26 to 27) to a HAM-Dtotal score at about 0 to 10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to4, 0 to 3, 0 to 2, or 1.8) after treatment with a compound describedherein, e.g., a compound of Formula (I). In some embodiments, thedecrease in the baseline HAM-D total score to HAM-D total score aftertreatment with a compound described herein, e.g., a compound of Formula(I), is at least 1, 2, 3, 4, 5, 7, 10, 25, 40, 50, or 100 fold). In someembodiments, the percentage decrease in the baseline HAM-D total scoreto HAM-D total score after treatment with a compound described herein,e.g., a compound of Formula (I), is at least 50% (e.g., 60%, 70%, 80%,or 90%). In some embodiments, the therapeutic effect is measured as adecrease in the HAM-D total score after treatment with a compounddescribed herein, e.g., a compound of Formula (I), relative to thebaseline HAM-D total score (e.g., 12, 24, 48 hours after administration;or 24, 48, 72, 96 hours or more; or 1 day, 2 days, 14 days, or more) isat least 10, 15, or 20 points.

In some embodiments, the method of treating a depressive disorder, e.g.,major depressive disorder provides a therapeutic effect (e.g., asmeasured by reduction in Hamilton Depression Score (HAM-D)) within 14,10, 4, 3, 2, or 1 days, or 24, 20, 16, 12, 10, or 8 hours or less. Insome embodiments, the method of treating the depressive disorder, e.g.,major depressive disorder, provides a therapeutic effect (e.g., asdetermined by a statistically significant reduction in HAM-D totalscore) within the first or second day of the treatment with a compounddescribed herein, e.g., a compound of Formula (I). In some embodiments,the method of treating the depressive disorder, e.g., major depressivedisorder, provides a therapeutic effect (e.g., as determined by astatistically significant reduction in HAM-D total score) within lessthan or equal to 14 days since the beginning of the treatment with acompound described herein, e.g., a compound of Formula (I). In someembodiments, the method of treating the depressive disorder, e.g., majordepressive disorder, provides a therapeutic effect (e.g., as determinedby a statistically significant reduction in HAM-D total score) withinless than or equal to 21 days since the beginning of the treatment witha compound described herein, e.g., a compound of Formula (I). In someembodiments, the method of treating the depressive disorder, e.g., majordepressive disorder, provides a therapeutic effect (e.g., as determinedby a statistically significant reduction in HAM-D total score) withinless than or equal to 28 days since the beginning of the treatment witha compound described herein, e.g., a compound of Formula (I). In someembodiments, the therapeutic effect is a decrease from baseline in HAM-Dtotal score after treatment with a compound described herein, e.g., acompound of Formula (I) (e.g., treatment with a compound describedherein, e.g., a compound of Formula (I), once a day for 14 days). Insome embodiments, the HAM-D total score of the subject before treatmentwith a compound described herein, e.g., a compound of Formula (I), is atleast 24. In some embodiments, the HAM-D total score of the subjectbefore treatment with a compound described herein, e.g., a compound ofFormula (I), is at least 18. In some embodiments, the HAM-D total scoreof the subject before treatment with a compound described herein, e.g.,a compound of Formula (I), is between and including 14 and 18. In someembodiments, the decrease in HAM-D total score after treating thesubject with a compound described herein, e.g., a compound of Formula(I), relative to the baseline HAM-D total score is at least 10. In someembodiments, the decrease in HAM-D total score after treating thesubject with a compound described herein, e.g., a compound of Formula(I), relative to the baseline HAM-D total score is at least 15 (e.g., atleast 17). In some embodiments, the HAM-D total score associated withtreating the subject with a compound described herein, e.g., a compoundof Formula (I), is no more than a number ranging from 6 to 8. In someembodiments, the HAM-D total score associated with treating the subjectwith a compound described herein, e.g., a compound of Formula (I), is nomore than 7.

In some embodiments, the method provides therapeutic effect (e.g., asmeasured by reduction in Clinical Global Impression-Improvement Scale(CGI)) within 14, 10, 4, 3, 2, or 1 days, or 24, 20, 16, 12, 10, or 8hours or less. In some embodiments, the CNS-disorder is a depressivedisorder, e.g., major depressive disorder. In some embodiments, themethod of treating the depressive disorder, e.g., major depressivedisorder provides a therapeutic effect within the second day of thetreatment period. In some embodiments, the therapeutic effect is adecrease from baseline in CGI score at the end of a treatment period(e.g., 14 days after administration).

In some embodiments, the method provides therapeutic effect (e.g., asmeasured by reduction in Montgomery-Asberg Depression Rating Scale(MADRS)) within 14, 10, 4, 3, 2, or 1 days, or 24, 20, 16, 12, 10, or 8hours or less. In some embodiments, the CNS-disorder is a depressivedisorder, e.g., major depressive disorder. In some embodiments, themethod of treating the depressive disorder, e.g., major depressivedisorder provides a therapeutic effect within the second day of thetreatment period. In some embodiments, the therapeutic effect is adecrease from baseline in MADRS score at the end of a treatment period(e.g., 14 days after administration).

A therapeutic effect for major depressive disorder can be determined bya reduction in Montgomery-Asberg Depression Rating Scale (MADRS) scoreexhibited by the subject. For example, the MADRS score can be reducedwithin 4, 3, 2, or 1 days; or 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, 8hours or less. The Montgomery-Asberg Depression Rating Scale (MADRS) isa ten-item diagnostic questionnaire (regarding apparent sadness,reported sadness, inner tension, reduced sleep, reduced appetite,concentration difficulties, lassitude, inability to feel, pessimisticthoughts, and suicidal thoughts) which psychiatrists use to measure theseverity of depressive episodes in patients with mood disorders.

In some embodiments, the method provides therapeutic effect (e.g., asmeasured by reduction in Edinburgh Postnatal Depression Scale (EPDS))within 4, 3, 2, 1 days; 24, 20, 16, 12, 10, 8 hours or less. In someembodiments, the therapeutic effect is an improvement measured by theEPDS.

In some embodiments, the method provides therapeutic effect (e.g., asmeasured by reduction in Generalized Anxiety Disorder 7-Item Scale(GAD-7)) within 4, 3, 2, 1 days; 24, 20, 16, 12, 10, 8 hours or less.

Anxiety Disorders

Provided herein are methods for treating anxiety disorders (e.g.,generalized anxiety disorder, panic disorder, obsessive compulsivedisorder, phobia, post-traumatic stress disorder). Anxiety disorder is ablanket term covering several different forms of abnormal andpathological fear and anxiety. Current psychiatric diagnostic criteriarecognize a wide variety of anxiety disorders.

Generalized anxiety disorder is a common chronic disorder characterizedby long-lasting anxiety that is not focused on any one object orsituation. Those suffering from generalized anxiety experiencenon-specific persistent fear and worry and become overly concerned witheveryday matters. Generalized anxiety disorder is the most commonanxiety disorder to affect older adults.

In panic disorder, a person suffers from brief attacks of intense terrorand apprehension, often marked by trembling, shaking, confusion,dizziness, nausea, difficulty breathing. These panic attacks, defined bythe APA as fear or discomfort that abruptly arises and peaks in lessthan ten minutes, can last for several hours and can be triggered bystress, fear, or even exercise; although the specific cause is notalways apparent. In addition to recurrent unexpected panic attacks, adiagnosis of panic disorder also requires that said attacks have chronicconsequences: either worry over the attacks' potential implications,persistent fear of future attacks, or significant changes in behaviorrelated to the attacks. Accordingly, those suffering from panic disorderexperience symptoms even outside of specific panic episodes. Often,normal changes in heartbeat are noticed by a panic sufferer, leadingthem to think something is wrong with their heart or they are about tohave another panic attack. In some cases, a heightened awareness(hypervigilance) of body functioning occurs during panic attacks,wherein any perceived physiological change is interpreted as a possiblelife threatening illness (i.e. extreme hypochondriasis).

Obsessive compulsive disorder is a type of anxiety disorder primarilycharacterized by repetitive obsessions (distressing, persistent, andintrusive thoughts or images) and compulsions (urges to perform specificacts or rituals). The OCD thought pattern may be likened tosuperstitions insofar as it involves a belief in a causativerelationship where, in reality, one does not exist. Often the process isentirely illogical; for example, the compulsion of walking in a certainpattern may be employed to alleviate the obsession of impending harm.And in many cases, the compulsion is entirely inexplicable, simply anurge to complete a ritual triggered by nervousness. In a minority ofcases, sufferers of OCD may only experience obsessions, with no overtcompulsions; a much smaller number of sufferers experience onlycompulsions.

The single largest category of anxiety disorders is that of phobia,which includes all cases in which fear and anxiety is triggered by aspecific stimulus or situation. Sufferers typically anticipateterrifying consequences from encountering the object of their fear,which can be anything from an animal to a location to a bodily fluid.

Post-traumatic stress disorder or PTSD is an anxiety disorder whichresults from a traumatic experience. Post-traumatic stress can resultfrom an extreme situation, such as combat, rape, hostage situations, oreven serious accident. It can also result from long term (chronic)exposure to a severe stressor, for example soldiers who endureindividual battles but cannot cope with continuous combat. Commonsymptoms include flashbacks, avoidant behaviors, and depression.

Women's Health Disorders

Provided herein are methods for treating conditions or disorders relatedto women's health. Conditions or disorders related to women's healthinclude, but are not limited to, gynecological health and disorders(e.g., premenstrual syndrome (PMS), premenstrual dysphoric disorder(PMDD)), pregnancy issues (e.g., miscarriage, abortion), infertility andrelated disorders (e.g., polycystic ovary syndrome (PCOS)), otherdisorders and conditions, and issues related to women's overall healthand wellness (e.g., menopause).

Gynecological health and disorders affecting women include menstruationand menstrual irregularities; urinary tract health, including urinaryincontinence and pelvic floor disorders; and such disorders as bacterialvaginosis, vaginitis, uterine fibroids, and vulvodynia.

Premenstrual syndrome (PMS) refers to physical and emotional symptomsthat occur in the one to two weeks before a women's period. Symptomsvary but can include bleeding, mood swings, tender breasts, foodcravings, fatigue, irritability, acne, and depression.

Premenstrual dysphoric disorder (PMDD) is a severe form of PMS. Thesymptoms of PMDD are similar to PMS but more severe and may interferewith work, social activity, and relationships. PMDD symptoms includemood swings, depressed mood or feelings of hopelessness, marked anger,increased interpersonal conflicts, tension and anxiety, irritability,decreased interest in usual activities, difficulty concentrating,fatigue, change in appetite, feeling out of control or overwhelmed,sleep problems, physical problems (e.g., bloating, breast tenderness,swelling, headaches, joint or muscle pain).

Pregnancy issues include preconception care and prenatal care, pregnancyloss (miscarriage and stillbirth), preterm labor and premature birth,sudden infant death syndrome (SIDS), breastfeeding, and birth defects.

Miscarriage refers to a pregnancy that ends on its own, within the first20 weeks of gestation.

Abortion refers to the deliberate termination of a pregnancy, which canbe performed during the first 28 weeks of pregnancy.

Infertility and related disorders include uterine fibroids, polycysticovary syndrome, endometriosis, and primary ovarian insufficiency.

Polycystic ovary syndrome (PCOS) refers to an endocrine system disorderamong women of reproductive age. PCOS is a set of symptoms resultingfrom an elevated male hormone in women. Most women with PCOS grow manysmall cysts on their ovaries. Symptoms of PCOS include irregular or nomenstrual periods, heavy periods, excess body and facial hair, acne,pelvic pain, difficulty getting pregnant, and patches of thick, darker,velvety skin. PCOS may be associated with conditions including type 2diabetes, obesity, obstructive sleep apnea, heart disease, mooddisorders, and endometrial cancer.

Other disorders and conditions that affect only women include Turnersyndrome, Rett syndrome, and ovarian and cervical cancers.

Issues related to women's overall health and wellness include violenceagainst women, women with disabilities and their unique challenges,osteoporosis and bone health, and menopause.

Menopause refers to the 12 months after a woman's last menstrual periodand marks the end of menstrual cycles. Menopause typically occurs in awoman's 40s or 50s. Physical symptoms such as hot flashes and emotionalsymptoms of menopause may disrupt sleep, lower energy, or triggeranxiety or feelings of sadness or loss. Menopause includes naturalmenopause and surgical menopause, which is a type of induced menopausedue to an event such as surgery (e.g., hysterectomy, oophorectomy;cancer). It is induced when the ovaries are gravely damaged by, e.g.,radiation, chemotherapy, or other medications.

Epilepsy

The compound of Formula (I), or pharmaceutically acceptable salt, or apharmaceutically acceptable composition thereof, can be used in a methoddescribed herein, for example in the treatment of a disorder describedherein such as epilepsy, status epilepticus, or seizure.

Epilepsy is a brain disorder characterized by repeated seizures overtime. Types of epilepsy can include, but are not limited to generalizedepilepsy, e.g., childhood absence epilepsy, juvenile nyoclonic epilepsy,epilepsy with grand-mal seizures on awakening, West syndrome,Lennox-Gastaut syndrome, partial epilepsy, e.g., temporal lobe epilepsy,frontal lobe epilepsy, benign focal epilepsy of childhood.

Epileptogenesis

The compounds and methods described herein can be used to treat orprevent epileptogenesis. Epileptogenesis is a gradual process by which anormal brain develops epilepsy (a chronic condition in which seizuresoccur). Epileptogenesis results from neuronal damage precipitated by theinitial insult (e.g., status epilepticus).

Status Epilepticus (SE)

Status epilepticus (SE) can include, e.g., convulsive statusepilepticus, e.g., early status epilepticus, established statusepilepticus, refractory status epilepticus, super-refractory statusepilepticus; non-convulsive status epilepticus, e.g., generalized statusepilepticus, complex partial status epilepticus; generalized periodicepileptiform discharges; and periodic lateralized epileptiformdischarges. Convulsive status epilepticus is characterized by thepresence of convulsive status epileptic seizures, and can include earlystatus epilepticus, established status epilepticus, refractory statusepilepticus, super-refractory status epilepticus. Early statusepilepticus is treated with a first line therapy. Established statusepilepticus is characterized by status epileptic seizures which persistdespite treatment with a first line therapy, and a second line therapyis administered. Refractory status epilepticus is characterized bystatus epileptic seizures which persist despite treatment with a firstline and a second line therapy, and a general anesthetic is generallyadministered. Super refractory status epilepticus is characterized bystatus epileptic seizures which persist despite treatment with a firstline therapy, a second line therapy, and a general anesthetic for 24hours or more.

Non-convulsive status epilepticus can include, e.g., focalnon-convulsive status epilepticus, e.g., complex partial non-convulsivestatus epilepticus, simple partial non-convulsive status epilepticus,subtle non-convulsive status epilepticus; generalized non-convulsivestatus epilepticus, e.g., late onset absence non-convulsive statusepilepticus, atypical absence non-convulsive status epilepticus, ortypical absence non-convulsive status epilepticus.

The compound of Formula (I) or pharmaceutically acceptable salt, or apharmaceutically acceptable composition thereof, can also beadministered as a prophylactic to a subject having a CNS disorder e.g.,a traumatic brain injury, status epilepticus, e.g., convulsive statusepilepticus, e.g., early status epilepticus, established statusepilepticus, refractory status epilepticus, super-refractory statusepilepticus; non-convulsive status epilepticus, e.g., generalized statusepilepticus, complex partial status epilepticus; generalized periodicepileptiform discharges; and periodic lateralized epileptiformdischarges; prior to the onset of a seizure.

Seizure

A seizure is the physical findings or changes in behavior that occurafter an episode of abnormal electrical activity in the brain. The term“seizure” is often used interchangeably with “convulsion.” Convulsionsare when a person's body shakes rapidly and uncontrollably. Duringconvulsions, the person's muscles contract and relax repeatedly.

Based on the type of behavior and brain activity, seizures are dividedinto two broad categories: generalized and partial (also called local orfocal). Classifying the type of seizure helps doctors diagnose whetheror not a patient has epilepsy.

Generalized seizures are produced by electrical impulses from throughoutthe entire brain, whereas partial seizures are produced (at leastinitially) by electrical impulses in a relatively small part of thebrain. The part of the brain generating the seizures is sometimes calledthe focus.

There are six types of generalized seizures. The most common anddramatic, and therefore the most well-known, is the generalizedconvulsion, also called the grand-mal seizure. In this type of seizure,the patient loses consciousness and usually collapses. The loss ofconsciousness is followed by generalized body stiffening (called the“tonic” phase of the seizure) for 30 to 60 seconds, then by violentjerking (the “clonic” phase) for 30 to 60 seconds, after which thepatient goes into a deep sleep (the “postictal” or after-seizure phase).During grand-mal seizures, injuries and accidents may occur, such astongue biting and urinary incontinence.

Absence seizures cause a short loss of consciousness (just a fewseconds) with few or no symptoms. The patient, most often a child,typically interrupts an activity and stares blankly. These seizuresbegin and end abruptly and may occur several times a day. Patients areusually not aware that they are having a seizure, except that they maybe aware of “losing time.”

Myoclonic seizures consist of sporadic jerks, usually on both sides ofthe body. Patients sometimes describe the jerks as brief electricalshocks. When violent, these seizures may result in dropping orinvoluntarily throwing objects.

Clonic seizures are repetitive, rhythmic jerks that involve both sidesof the body at the same time.

Tonic seizures are characterized by stiffening of the muscles.

Atonic seizures consist of a sudden and general loss of muscle tone,particularly in the arms and legs, which often results in a fall.

Seizures described herein can include epileptic seizures; acuterepetitive seizures; cluster seizures; continuous seizures; unremittingseizures; prolonged seizures; recurrent seizures; status epilepticusseizures, e.g., refractory convulsive status epilepticus, non-convulsivestatus epilepticus seizures; refractory seizures; myoclonic seizures;tonic seizures; tonic-clonic seizures; simple partial seizures; complexpartial seizures; secondarily generalized seizures; atypical absenceseizures; absence seizures; atonic seizures; benign Rolandic seizures;febrile seizures; emotional seizures; focal seizures; gelastic seizures;generalized onset seizures; infantile spasms; Jacksonian seizures;massive bilateral myoclonus seizures; multifocal seizures; neonatalonset seizures; nocturnal seizures; occipital lobe seizures; posttraumatic seizures; subtle seizures; Sylvan seizures; visual reflexseizures; or withdrawal seizures. In some embodiments, the seizure is ageneralized seizure associated with Dravet Syndrome, Lennox-GastautSyndrome, Tuberous Sclerosis Complex, Rett Syndrome or PCDH19 FemalePediatric Epilepsy.

Movement Disorders

Also described herein are methods for treating a movement disorder. Asused herein, “movement disorders” refers to a variety of diseases anddisorders that are associated with hyperkinetic movement disorders andrelated abnormalities in muscle control. Exemplary movement disordersinclude, but are not limited to, Parkinson's disease and parkinsonism(defined particularly by bradykinesia), dystonia, chorea andHuntington's disease, ataxia, tremor (e.g., essential tremor), myoclonusand startle, tics and Tourette syndrome, Restless legs syndrome, stiffperson syndrome, and gait disorders.

Tremor

The methods described herein can be used to treat tremor, for examplethe compound of Formula (I) can be used to treat cerebellar tremor orintention tremor, dystonic tremor, essential tremor, orthostatic tremor,parkinsonian tremor, physiological tremor, psychogenic tremor, or rubraltremor. Tremor includes hereditary, degenerative, and idiopathicdisorders such as Wilson's disease, Parkinson's disease, and essentialtremor, respectively; metabolic diseases (e.g., thyroid-parathyroid-,liver disease and hypoglycemia); peripheral neuropathies (associatedwith Charcot-Marie-Tooth, Roussy-Levy, diabetes mellitus, complexregional pain syndrome); toxins (nicotine, mercury, lead, CO, Manganese,arsenic, toluene); drug-induced (narcoleptics, tricyclics, lithium,cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine,steroids, valproate, amiodarone, thyroid hormones, vincristine); andpsychogenic disorders. Clinical tremor can be classified intophysiologic tremor, enhanced physiologic tremor, essential tremorsyndromes (including classical essential tremor, primary orthostatictremor, and task- and position-specific tremor), dystonic tremor,parkinsonian tremor, cerebellar tremor, Holmes' tremor (i.e., rubraltremor), palatal tremor, neuropathic tremor, toxic or drug-inducedtremor, and psychogenic tremor.

Tremor is an involuntary, at times rhythmic, muscle contraction andrelaxation that can involve oscillations or twitching of one or morebody parts (e.g., hands, arms, eyes, face, head, vocal folds, trunk,legs).

Cerebellar tremor or intention tremor is a slow, broad tremor of theextremities that occurs after a purposeful movement. Cerebellar tremoris caused by lesions in or damage to the cerebellum resulting from,e.g., tumor, stroke, disease (e.g., multiple sclerosis, an inheriteddegenerative disorder).

Dystonic tremor occurs in individuals affected by dystonia, a movementdisorder in which sustained involuntary muscle contractions causetwisting and repetitive motions and/or painful and abnormal postures orpositions. Dystonic tremor may affect any muscle in the body. Dystonictremors occurs irregularly and often can be relieved by complete rest.

Essential tremor or benign essential tremor is the most common type oftremor. Essential tremor may be mild and nonprogressive in some, and maybe slowly progressive, starting on one side of the body but affect bothsides within 3 years. The hands are most often affected, but the head,voice, tongue, legs, and trunk may also be involved. Tremor frequencymay decrease as the person ages, but severity may increase. Heightenedemotion, stress, fever, physical exhaustion, or low blood sugar maytrigger tremors and/or increase their severity. Symptoms generallyevolve over time and can be both visible and persistent following onset.

Orthostatic tremor is characterized by fast (e.g., greater than 12 Hz)rhythmic muscle contractions that occurs in the legs and trunkimmediately after standing. Cramps are felt in the thighs and legs andthe patient may shake uncontrollably when asked to stand in one spot.Orthostatic tremor may occurs in patients with essential tremor.

Parkinsonian tremor is caused by damage to structures within the brainthat control movement. Parkinsonian tremor is often a precursor toParkinson's disease and is typically seen as a “pill-rolling” action ofthe hands that may also affect the chin, lips, legs, and trunk. Onset ofparkinsonian tremor typically begins after age 60. Movement starts inone limb or on one side of the body and can progress to include theother side.

Physiological tremor can occur in normal individuals and have noclinical significance. It can be seen in all voluntary muscle groups.Physiological tremor can be caused by certain drugs, alcohol withdrawal,or medical conditions including an overactive thyroid and hypoglycemia.The tremor classically has a frequency of about 10 Hz.

Psychogenic tremor or hysterical tremor can occur at rest or duringpostural or kinetic movement. Patient with psychogenic tremor may have aconversion disorder or another psychiatric disease.

Rubral tremor is characterized by coarse slow tremor which can bepresent at rest, at posture, and with intention. The tremor isassociated with conditions that affect the red nucleus in the midbrain,classical unusual strokes.

Parkinson's Disease affects nerve cells in the brain that producedopamine. Symptoms include muscle rigidity, tremors, and changes inspeech and gait. Parkinsonism is characterized by tremor, bradykinesia,rigidity, and postural instability. Parkinsonism shares symptoms foundin Parkinson's Disease, but is a symptom complex rather than aprogressive neurodegenerative disease.

Dystonia is a movement disorder characterized by sustained orintermittent muscle contractions causing abnormal, often repetitivemovements or postures. Dystonic movements can be patterned, twisting,and may be tremulous. Dystonia is often initiated or worsened byvoluntary action and associated with overflow muscle activation.

Chorea is a neurological disorder characterized by jerky involuntarymovements typically affecting the shoulders, hips, and face.Huntington's Disease is an inherited disease that causes nerve cells inthe brain to waste away. Symptoms include uncontrolled movements,clumsiness, and balance problems. Huntington's disease can hinder walk,talk, and swallowing.

Ataxia refers to the loss of full control of bodily movements, and mayaffect the fingers, hands, arms, legs, body, speech, and eye movements.

Myloclonus and Startle is a response to a sudden and unexpectedstimulus, which can be acoustic, tactile, visual, or vestibular.

Tics are an involuntary movement usually onset suddenly, brief,repetitive, but non-rhythmical, typically imitating normal behavior andoften occurring out of a background of normal activity. Tics can beclassified as motor or vocal, motor tics associated with movements whilevocal tics associated with sound. Tics can be characterized as simple orcomplex. For example simple motor tics involve only a few musclesrestricted to a specific body part. Tourette Syndrome is an inheritedneuropsychiatric disorder with onset in childhood, characterized bymultiple motor tics and at least one vocal tic.

Restless Legs Syndrome is a neurologic sensorimotor disordercharacterized by an overwhelming urge to move the legs when at rest.

Stiff Person Syndrome is a progressive movement disorder characterizedby involuntary painful spasms and rigidity of muscles, usually involvingthe lower back and legs. Stiff-legged gait with exaggerated lumbarhyperlordosis typically results. Characteristic abnormality on EMGrecordings with continuous motor unit activity of the paraspinal axialmuscles is typically observed. Variants include “stiff-limb syndrome”producing focal stiffness typically affecting distal legs and feet.

Gait disorders refer to an abnormality in the manner or style ofwalking, which results from neuromuscular, arthritic, or other bodychanges. Gait is classified according to the system responsible forabnormal locomotion, and include hemiplegic gait, diplegic gait,neuropathic gait, myopathic gait, parkinsonian gait, choreiform gait,ataxic gait, and sensory gait.

Anesthesia Sedation

Anesthesia is a pharmacologically induced and reversible state ofamnesia, analgesia, loss of responsiveness, loss of skeletal musclereflexes, decreased stress response, or all of these simultaneously.These effects can be obtained from a single drug which alone providesthe correct combination of effects, or occasionally with a combinationof drugs (e.g., hypnotics, sedatives, paralytics, analgesics) to achievevery specific combinations of results. Anesthesia allows patients toundergo surgery and other procedures without the distress and pain theywould otherwise experience.

Sedation is the reduction of irritability or agitation by administrationof a pharmacological agent, generally to facilitate a medical procedureor diagnostic procedure.

Sedation and analgesia include a continuum of states of consciousnessranging from minimal sedation (anxiolysis) to general anesthesia.

Minimal sedation is also known as anxiolysis. Minimal sedation is adrug-induced state during which the patient responds normally to verbalcommands. Cognitive function and coordination may be impaired.Ventilatory and cardiovascular functions are typically unaffected.

Moderate sedation/analgesia (conscious sedation) is a drug-induceddepression of consciousness during which the patient respondspurposefully to verbal command, either alone or accompanied by lighttactile stimulation. No interventions are usually necessary to maintaina patent airway. Spontaneous ventilation is typically adequate.Cardiovascular function is usually maintained.

Deep sedation/analgesia is a drug-induced depression of consciousnessduring which the patient cannot be easily aroused, but respondspurposefully (not a reflex withdrawal from a painful stimulus) followingrepeated or painful stimulation. Independent ventilatory function may beimpaired and the patient may require assistance to maintain a patentairway. Spontaneous ventilation may be inadequate. Cardiovascularfunction is usually maintained.

General anesthesia is a drug-induced loss of consciousness during whichthe patient is not arousable, even to painful stimuli. The ability tomaintain independent ventilatory function is often impaired andassistance is often required to maintain a patent airway. Positivepressure ventilation may be required due to depressed spontaneousventilation or drug-induced depression of neuromuscular function.Cardiovascular function may be impaired.

Sedation in the intensive care unit (ICU) allows the depression ofpatients' awareness of the environment and reduction of their responseto external stimulation. It can play a role in the care of thecritically ill patient, and encompasses a wide spectrum of symptomcontrol that will vary between patients, and among individualsthroughout the course of their illnesses. Heavy sedation in criticalcare has been used to facilitate endotracheal tube tolerance andventilator synchronization, often with neuromuscular blocking agents.

In some embodiments, sedation (e.g., long-term sedation, continuoussedation) is induced and maintained in the ICU for a prolonged period oftime (e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 week, 3 weeks, 1month, 2 months). Long-term sedation agents may have long duration ofaction. Sedation agents in the ICU may have short elimination half-life.

Procedural sedation and analgesia, also referred to as conscioussedation, is a technique of administering sedatives or dissociativeagents with or without analgesics to induce a state that allows asubject to tolerate unpleasant procedures while maintainingcardiorespiratory function.

Also described herein are methods of ameliorating one or more symptomsof a respiratory condition in a subject, comprising administering to thesubject an effective amount of a compound or pharmaceutical compositiondescribed herein (e.g., a compound of Formula I, or a pharmaceuticalsalt thereof, or a composition comprising a compound of Formula I, or apharmaceutically acceptable salt thereof).

In one aspect, provided herein is a method of treating a subject whereinthe subject exhibits one or more symptoms of a respiratory conditionand/or has been diagnosed with a respiratory condition, comprisingadministering to said subject an effective amount of a compound orpharmaceutical composition described herein (e.g., a compound of FormulaI, or a pharmaceutical salt thereof, or a composition comprising acompound of Formula I, or a pharmaceutically acceptable salt thereof).

In some embodiments, the present disclosure contemplates a method oftreating a subject comprising administering to said subject a compoundor pharmaceutical composition described herein (e.g., a compound ofFormula I, or a pharmaceutical salt thereof, or a composition comprisinga compound of Formula I, or a pharmaceutically acceptable salt thereof),wherein the subject has a respiratory condition.

In some embodiments, administration of a compound or pharmaceuticalcomposition described herein (e.g., a compound of Formula I, or apharmaceutical salt thereof, or a composition comprising a compound ofFormula I, or a pharmaceutically acceptable salt thereof) to a subjectexhibiting symptoms of a respiratory condition, may result in thereduction of the severity of one or more symptoms of a respiratorycondition or retard or slow the progression of one or more symptoms of arespiratory condition.

In some embodiments, a subject with a respiratory condition has been oris being treated with mechanical ventilation or oxygen. In someembodiments, a subject with a respiratory condition has been or is beingtreated with mechanical ventilation.

In some embodiments, a compound or pharmaceutical composition describedherein (e.g., a compound of Formula I, or a pharmaceutical salt thereof,or a composition comprising a compound of Formula I, or apharmaceutically acceptable salt thereof) is administered to a subjectthat is being or has been treated with mechanical ventilation. In someembodiments, administration of a compound or pharmaceutical compositiondescribed herein (e.g., a compound of Formula I, or a pharmaceuticalsalt thereof, or a composition comprising a compound of Formula I, or apharmaceutically acceptable salt thereof) continues throughout asubject's treatment with mechanical ventilation. In some embodiments,administration of a compound or pharmaceutical composition describedherein (e.g., a compound of Formula I, or a pharmaceutical salt thereof,or a composition comprising a compound of Formula I, or apharmaceutically acceptable salt thereof) continues after a subject hasended treatment with mechanical ventilation.

In some embodiments, a compound or pharmaceutical composition describedherein (e.g., a compound of Formula I, or a pharmaceutical salt thereof,or a composition comprising a compound of Formula I, or apharmaceutically acceptable salt thereof) is administered to a subjectwho is receiving or has received treatment with a sedative. In someembodiments, a sedative is propofol or a benzodiazepine.

In some embodiments, the present disclosure includes administering to asubject in need thereof a compound or pharmaceutical compositiondescribed herein (e.g., a compound of Formula I, or a pharmaceuticalsalt thereof, or a composition comprising a compound of Formula I, or apharmaceutically acceptable salt thereof) in an amount sufficient toincrease oxygen saturation in blood. In some embodiments, oxygensaturation in blood is measured using pulse oximetry.

In some embodiments, the present disclosure contemplates a method oftreating a cytokine storm in a patient. In some embodiments a method oftreating a cytokine storm comprising the step of administering to thepatient a compound or pharmaceutical composition described herein (e.g.,a compound of Formula I, or a pharmaceutical salt thereof, or acomposition comprising a compound of Formula I, or a pharmaceuticallyacceptable salt thereof). In some embodiments, a symptom of a cytokinestorm is lung inflammation. In some embodiments, a patient undergoing acytokine storm has acute respiratory distress syndrome (ARDS).

Respiratory Condition

In some embodiments, a subject with a respiratory condition suffers fromrespiratory distress. In some embodiments, respiratory distress includesacute respiratory distress.

In some embodiments, a subject with a respiratory condition may exhibitone or more symptoms selected from the group consisting of airwayhyper-responsiveness, inflammation of lung tissue, lunghypersensitivity, and inflammation-related pulmonary pain.

In some embodiments a subject with a respiratory condition may exhibitinflammation of lung tissue. In some embodiments, inflammation of lungtissue is bronchitis or bronchiectasis. In some embodiments,inflammation of lung tissue is pneumonia. In some embodiments, pneumoniais ventilator-associated pneumonia or hospital-acquired pneumonia. Insome embodiments, pneumonia is ventilator-associated pneumonia.

In some embodiments, administration of the compound or pharmaceuticalcomposition described herein to a subject exhibiting symptoms of arespiratory condition, results in reduction of the severity ofrespiratory distress in a subject with a respiratory condition or retardor slow the progression of respiratory distress in a subject with arespiratory condition.

In some embodiments, administration of a compound or pharmaceuticalcomposition described herein (e.g., a compound of Formula I, or apharmaceutical salt thereof, or a composition comprising a compound ofFormula I, or a pharmaceutically acceptable salt thereof) to a subjectexhibiting symptoms of a respiratory condition, results in reduction ofthe severity of airway hyper-responsiveness in a subject with a diseaseassociated with a coronavirus or retard or slow the progression ofairway hyper-responsiveness in a subject with a respiratory condition.

In some embodiments, administration of a compound or pharmaceuticalcomposition described herein (e.g., a compound of Formula I, or apharmaceutical salt thereof, or a composition comprising a compound ofFormula I, or a pharmaceutically acceptable salt thereof) to a subjectexhibiting symptoms of a respiratory condition, results in reduction ofthe severity of inflammation of lung tissue in a subject with arespiratory condition or retard or slow the progression of inflammationof lung tissue in a subject with a respiratory condition. In someembodiments, administration of a compound or pharmaceutical compositiondescribed herein (e.g., a compound of Formula I, or a pharmaceuticalsalt thereof, or a composition comprising a compound of Formula I, or apharmaceutically acceptable salt thereof) to a subject exhibitingsymptoms of a respiratory condition, results in reduction of theseverity of pneumonia in a subject with a respiratory condition orretard or slow the progression of pneumonia in a subject with arespiratory condition.

In some embodiments, administration of a compound or pharmaceuticalcomposition described herein (e.g., a compound of Formula I, or apharmaceutical salt thereof, or a composition comprising a compound ofFormula I, or a pharmaceutically acceptable salt thereof) to a subjectexhibiting symptoms of a respiratory condition, results in reduction ofthe severity of lung hypersensitivity in a subject with a respiratorycondition or retard or slow the progression of lung hypersensitivity ina subject with a respiratory condition.

In some embodiments, administration of a compound or pharmaceuticalcomposition described herein (e.g., a compound of Formula I, or apharmaceutical salt thereof, or a composition comprising a compound ofFormula I, or a pharmaceutically acceptable salt thereof) to a subjectexhibiting symptoms of a respiratory condition, results in reduction ofthe severity of inflammation-related pulmonary pain in a subject with arespiratory condition or retard or slow the progression ofinflammation-related pulmonary pain in a subject with a respiratorycondition.

In some embodiments, a subject with a respiratory condition isundergoing or has undergone treatment for an infection, fibrosis, afibrotic episode, chronic obstructive pulmonary disease, Sarcoidosis (orpulmonary sarcoidosis) or asthma/asthma-related inflammation.

In some embodiments, a subject exhibits symptoms of and/or has beendiagnosed with asthma. In some embodiments, a subject is or hasundergone an asthmatic attack.

In some embodiments, a subject is undergoing or has undergone treatmentfor fibrosis or a fibrotic episode. In some embodiments, the fibrosis iscystic fibrosis.

In some embodiments, a respiratory condition is the result of and/orrelated to a disease or condition selected from the group consisting ofcystic fibrosis, asthma, smoke induced COPD, chronic bronchitis,rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency,male infertility caused by congenital bilateral absence of the vasdeferens (CBAVD), mild pulmonary disease, pulmonary sarcoidosis,idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA),liver disease, hereditary emphysema, hereditary hemochromatosis,coagulation-fibrinolysis deficiencies, such as protein C deficiency,Type 1 hereditary angioedema, lipid processing deficiencies, such asfamilial hypercholesterolemia, Type 1 chylomicronemia,abetalipoproteinemia, lysosomal storage diseases, such as I-celldisease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs,Crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, Diabetesmellitus, Laron dwarfism, myleoperoxidase deficiency, primaryhypoparathyroidism, melanoma, glycanosis CDG type 1, congenitalhyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia,ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, neprogenic DI,Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease,neurodegenerative diseases such as Alzheimer's disease, Parkinson'sdisease, amyotrophic lateral sclerosis, progressive supranuclear palsy,Pick's disease, several polyglutamine neurological disorders such asHuntington, spinocerebellar ataxia type I, spinal and bulbar muscularatrophy, dentatorubal pallidoluysian, and myotonic dystrophy, as well asspongiform encephalopathies, such as hereditary Creutzfeldt-Jakobdisease (due to prion protein processing defect), Fabry disease,Straussler-Scheinker syndrome, COPD, dry-eye disease, or Sjogren'sdisease.

Infections

The present disclosure contemplates, among other things, treatment of asubject who has an infection. The present disclosure contemplates, amongother things, treatment of a subject who has a disease associated withan infection. In some embodiments, an infection is a viral infection ora bacterial infection. In some embodiments, an infection is a viralinfection. In some embodiments, an infection is a bacterial infection.

In some embodiments, a viral infection is an infection of a virusselected from the group consisting of a coronavirus, an influenza virus,human rhinovirus, a human parainfluenza virus, human metapneumovirus anda hantavirus. In some embodiments, a virus is a coronavirus. In someembodiments, a coronavirus is selected from the group consisting ofSARS-CoV, SARS-CoV-2, and MERS-CoV.

The present disclosure contemplates, among other things, treatment of asubject who has a disease associated with coronavirus. In someembodiments, a disease associated with a coronavirus is selected fromthe group consisting of coronavirus disease 2019 (COVID-19), severeacute respiratory syndrome (SARS) and Middle East respiratory syndrome(MERS). In some embodiments, a disease associated with a coronavirus isselected from the group consisting of COVID-19. In some embodiments, acoronavirus is selected from a group consisting of SARS-CoV-1,SARS-CoV-2, and 2012-nCoV. In some embodiments, a coronavirus isSARS-CoV-2.

In some embodiments, a bacterial infection is an infection of a bacteriaselected from the group consisting of Streptococcus pneumoniae,Chlamydia pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, andHaemophilus influenzae. In some embodiments, Staphylococcus aureus ismethicillin-resistant Staphylococcus aureus.

EXAMPLES

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. The synthetic andbiological examples described in this application are offered toillustrate the compounds, pharmaceutical compositions, and methodsprovided herein and are not to be construed in any way as limiting theirscope.

Materials and Methods

The compounds provided herein can be prepared from readily availablestarting materials using the following general methods and procedures.It will be appreciated that where typical or preferred processconditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. The choice of asuitable protecting group for a particular functional group as well assuitable conditions for protection and deprotection are well known inthe art. For example, numerous protecting groups, and their introductionand removal, are described in T. W. Greene and P. G. M. Wuts, ProtectingGroups in Organic Synthesis, Second Edition, Wiley, New York, 1991, andreferences cited therein.

The compounds provided herein may be isolated and purified by knownstandard procedures. Such procedures include (but are not limited to)trituration, column chromatography, HPLC, or supercritical fluidchromatography (SFC). The following schemes are presented with detailsas to the preparation of representative oxysterols that have been listedherein. The compounds provided herein may be prepared from known orcommercially available starting materials and reagents by one skilled inthe art of organic synthesis. Exemplary chiral columns available for usein the separation/purification of the enantiomers/diastereomers providedherein include, but are not limited to, CHIRALPAK® AD-10, CHIRALCEL® OB,CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF,CHIRALCEL® OG, CHIRALCEL® OJ and CHIRALCEL® OK.

¹H-NMR reported herein (e.g., for the region between δ (ppm) of about0.5 to about 4 ppm) will be understood to be an exemplary interpretationof the NMR spectrum (e.g., exemplary peak integratations) of a compound.

Abbreviations: PE: petroleum ether; EtOAc: ethyl acetate; THF:tetrahydrofuran; PCC: pyridinium chlorochromate; TLC: thin layerchromatography; PCC: pyridinium chlorochromate; t-BuOK: potassiumtert-butoxide; 9-BBN: 9-borabicyclo[3.3.1]nonane; Pd(t-Bu₃P)₂:bis(tri-tert-butylphosphine)palladium(0); AcCl: acetyl chloride;i-PrMgCl: Isopropylmagnesium chloride; TBSCl:tert-Butyl(chloro)dimethylsilane; (i-PrO)₄Ti: titaniumtetraisopropoxide; BHT: 2,6-di-t-butyl-4-methylphenoxide; Me: methyl;i-Pr: iso-propyl; t-Bu: tert-butyl; Ph: phenyl; Et: ethyl; Bz: benzoyl;BzCl: benzoyl chloride; CsF: cesium fluoride; DCC:dicyclohexylcarbodiimide; DCM: dichloromethane; DMAP:4-dimethylaminopyridine; DMP: Dess-Martin periodinane; EtMgBr:ethylmagnesium bromide; EtOAc: ethyl acetate; TEA: triethylamine; AlaOH:alanine; Boc: t-butoxycarbonyl. Py: pyridine; TBAF:tetra-n-butylammonium fluoride; THF: tetrahydrofuran; TBS:t-butyldimethylsilyl; TMS: trimethylsilyl; TMSCF₃:(Trifluoromethyl)trimethylsilane; Ts: p-toluenesulfonyl; Bu: butyl;Ti(OiPr)₄: tetraisopropoxytitanium; LAH: Lithium Aluminium Hydride; LDA:lithium diisopropylamide; LiOH·H₂O: lithium hydroxide hydrates; MAD:methyl aluminum bis(2,6-di-t-butyl-4-methylphenoxide); MeCN:acetonitrile; NBS: N-bromosuccinimide; Na₂SO₄: sodium sulfate; Na₂S₂O₃:sodium thiosulfate; MeCN: acetonitrile; MeOH: methanol; Boc:t-butoxycarbonyl; MTBE: methyl tert-butyl ether; K-selectride: Potassiumtri(s-butyl)borohydride; 9-BBNdimer: 9-borabicyclo(3.3.1)nonane(dimer);DIPEA: diisopropylethylamine; DMF: dimethylformamide; FA: formic acid;SM: starting material.

EXAMPLE 1 & 2: Synthesis of1-((R)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile(1) &1-((S)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile(2)

Synthesis of 1-1

To a suspension of Ph₃PMeBr (10 g, 28.2 mmol) in anhydrous THE (40 mL)was added t-BuOK (3.16 g, 28.2 mmol) at 25° C. under N₂. After stirringat 50° C. for 30 min, a solution of 1-0 (3 g, 9.4 mmol) in anhydrous THE(10 mL) was added dropwise. After stirring at 60° C. for 1 h, themixture was poured into 10% NH₄Cl (50 mL) and stirred for 10 min. Theaqueous phase was extracted with EtOAc (3×50 mL). The combine organicsolution was washed with saturated brine (2×50 mL), filtered andconcentrated. The residue was dissolved in MeOH (50 mL) and water (50mL). The resulting compound was collected by filtration and dried togive desired 1-1 (2.97 g, 100%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 4.84 (s,1H), 4.70 (s, 1H), 2.08-1.99 (m, 1H), 1.90-1.78 (m, 4H), 1.75 (s, 3H),1.74-1.56 (m, 5H), 1.49-1.28 (m, 8H), 1.26 (s, 3H), 1.23-1.13 (m, 3H),1.11-0.97 (m, 3H), 0.57 (s, 3H)

Synthesis of 1-2

To a solution of 1-1 (500 mg, 1.57 mmol) in DCM (10 mL) was added mCPBA(541 mg, 3.14 mmol) at 25° C. After stirring at 40° C. for 1 h, themixture was quenched with saturated NaHCO₃ aqueous (100 mL) at 15° C.The DCM phase was separated and washed with saturated NaHCO₃/Na₂S₂O₃aqueous (1:1, 2×100 mL), brine (100 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under vacuum to give a residue, which waspurified by flash column (10˜20% of EtOAc in PE) to give 1-2 (685 mg).

Synthesis of 1 & 2

To a solution of 1-2 (685 mg, 2.05 mmol) in DMF (10 mL) was added1H-pyrazole-4-carbonitrile (285 mg, 3.07 mmol) and Cs₂CO₃ (3.32 g, 10.2mmol) at 20° C. After stirring at 120° C. for 2 h, the mixture wasdiluted with water (100 mL) and extracted with EtOAc (2×50 mL). Thecombined organic solution was separated, concentrated and purified byflash column (30˜65% EtOAc in PE) to give a mixture of epimers (600 mg,69%). The epimers were separated by HPLC (Column: XtimateC18 150*25 mm*5μm; Condition: water (0.225% FA)-ACN; Begin B: 74%; End B: 74%.) toafford 1 (133 mg) and 2 (259.2 mg).

1: ¹H NMR (400 MHz, CDCl₃) δ7.93 (s, 1H), 7.82 (s, 1H), 4.35 (d, J=14.0Hz, 1H), 4.08 (d, J=13.6 Hz, 1H), 2.51 (s, 1H), 2.05-1.98 (m, 1H),1.83-1.71 (m, 5H), 1.70-1.62 (m, 3H), 1.51-1.41 (m, 3H), 1.40 (br s,2H), 1.37-1.27 (m, 3H), 1.26 (s, 3H), 1.23-1.20 (m, 1H), 1.19-1.10 (m,2H), 1.10-1.02 (m, 4H), 0.97 (s, 3H), 0.92 (s, 3H); LC-ELSD/MS purity99%, 100% de based on H-NMR; MS ESI calcd. for C₂₆H₃₆N₃[M−2H₂O+H]⁺390.3, found 390.3.

2: ¹H NMR (400 MHz, CDCl₃) δ7.89 (s, 1H), 7.80 (s, 1H), 4.22-4.13 (m,1H), 4.06-3.94 (m, 1H), 2.31 (br s, 1H), 2.10-2.02 (m, 1H), 1.96-1.82(m, 2H), 1.80 (br d, J=6.8 Hz, 2H), 1.70-1.61 (m, 4H), 1.40 (br s, 8H),1.26 (s, 3H), 1.25-1.09 (m, 5H), 1.09 (s, 3H), 1.07-1.00 (m, 2H), 0.87(s, 3H); LC-ELSD/MS purity 99%, 100% de based on H-NMR; MS ESI calcd.for C₂₆H₃₆N₃[M−2H₂O+H]⁺ 390.3, found 390.3.

EXAMPLES 3 & 4: Synthesis of1-((S)-2-((3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile(3) &1-((R)-2-((3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile(4)

Synthesis of 3-1

To a solution of 3-0 (10 g, 25.4 mmol, reported in patent‘WO2016/134301, 2016, A2’) in DCM (100 mL) was added silica gel (10 g)and PCC (8.17 g, 38 mmol) at 0° C. After stirring at 25° C. for 1 h, thesuspension was filtered, and the filter cake was washed with DCM (2×100mL). The combined filtrate was concentrated to give 3-1 (10 g). ¹H NMR(400 MHz, CDCl₃) δ_(H) 9.56 (s, 1H), 4.00-3.80 (m, 8H), 2.24-1.88 (m,5H), 1.87-1.70 (m, 5H), 1.46-1.35 (m, 5H), 1.33-0.99 (m, 5H), 0.92 (s,3H), 0.89-0.69 (m, 2H).

Synthesis of 3-2

To a mixture of MePPh₃Br (27.1 g, 76.1 mmol) in THE (100 mL) was addedt-BuOK (8.53 g, 76.1 mmol) at 15° C. under N₂. After stirring at 50° C.for 30 min, 3-1 (9.91 g, 25.4 mmol) was added in portions below 50° C.After stirring at 50° C. for 1 h, the reaction mixture was quenched with10% NH₄Cl aqueous (200 mL) at 15° C. The organic layer was separated andthe aqueous was extracted with EtOAc (300 mL). The combined organicphase was concentrated under vacuum to give a residue, which waspurified by silica gel chromatography (PE/EtOAc=20/1 to 5/1) to afford3-2 (5 g, 50.7%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 6.32-6.25 (m, 1H),5.15-4.94 (m, 2H), 3.95-3.80 (m, 8H) 2.02-1.72 (m, 6H), 1.69-1.61 (m,1H), 1.59-1.31 (m, 12H), 1.21-1.04 (m, 3H), 0.80 (s, 3H).

Synthesis of 3-3

To a solution of 3-2 (15 g, 12.8 mmol) in THF (30 mL) were added aq. HCl(38.6 mL, 2M, 77.2 mmol) and at 25° C. under N₂. After stirring at 25°C. for 5 h, the mixture was quenched with saturated NaHCO₃ (100 mL). Theorganic layer was separated, and the aqueous layer was extracted withEtOAc (2×100 mL). The combined organic layer was washed with brine (30mL), dried over anhydrous Na₂SO₄, filtered and concentrated to give 3-3(9.3 g, 80.8%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 6.32-6.25 (m, 1H), 5.19(d, J=11.2 Hz, 1H), 5.09 (d, J=18.0 Hz, 1H), 2.79-2.64 (m, 1H),2.54-2.13 (m, 5H), 2.13-2.05 (m, 3H), 2.02-1.79 (m, 3H), 1.69-1.50 (m,6H), 1.37-1.23 (m, 4H), 0.87 (s, 3H).

Synthesis of 3-4

To a solution of 3-3 (11 g, 36.6 mmol) in THF (200 mL) was added Pd/C(wet, 50%, 2 g) under N₂. The suspension was degassed under vacuum andpurged with H₂ for three times. After stirring under H₂ (30 psi) at 25°C. for 16 h, the reaction mixture was filtered through a pad of Celiteand washed with THE (2×100 mL). The residue was triturated from PE (300mL) to give 3-4 (12 g). ¹H NMR (400 MHz, CDCl₃) δ_(H) 2.67 (t, J=13.60Hz, 1H), 2.52-2.06 (m, 5H), 2.00-1.91 (m, 1H), 1.89-1.48 (m, 12H),1.39-1.19 (m, 5H), 0.87 (s, 3H), 0.80 (t, J=7.53 Hz, 3 H).

Synthesis of 3-5

To a solution of BHT (26 g, 118 mmol) in toluene (60 mL) under nitrogenat 0° C. was added AlMe₃ (2 M in toluene, 29.7 mL, 59.4 mmol) dropwise.After stirring at 15° C. for 1 h, a solution of 3-4 (6.0 g, 19.8 mmol)in DCM (10 mL) was added dropwise at −70° C. After stirring at −70° C.for 1 h under N₂, MeMgBr (19.8 mL, 59.4 mmol, 3M in ethyl ether) wasadded dropwise at −70° C. After stirring at −70° C. for 4 h, thereaction mixture was poured into saturated 20% citric acid (300 mL)below 10° C. The reaction mixture was extracted with EtOAc (2×100 mL).The combined organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by a silica gel column(PE/EtOAc=0-20%) to give 3-5 (5.6 g, 88.8%).

¹H NMR (400 MHz, CDCl₃) δ_(H) 2.50-2.37 (m, 1H), 2.13-2.04 (m, 1H),2.04-1.81 (m, 3H), 1.81-1.62 (m, 5H), 1.62-1.47 (m, 5H), 1.46-1.28 (m,6H), 1.25 (s, 3H), 1.24-1.11 (m, 4H), 0.84 (s, 3H), 0.80 (t, J=7.60 Hz,3H).

Synthesis of 3-6

To a mixture of EtPPh₃Br (9.72 g, 26.2 mmol) in THF (50 mL) was addedt-BuOK (2.93 g, 26.2 mmol) at 15° C. under N₂. After stirring at 50° C.for 30 min, 3-5 (5.6 g, 17.5 mmol) was added in portions below 40° C.After stirring at 40° C. for 1 h, the reaction mixture was quenched with10% NH₄Cl aqueous (200 mL) at 15° C. The organic layer was collected andthe aqueous layer was extracted with EtOAc (300 mL). The combinedorganic phase was concentrated under vacuum to give a residue, which waspurified by silica gel chromatography (PE/EtOAc=20/1 to 5/1) to afford3-6 (4.9 g, 84.7%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 5.15-5.05 (m, 1H),2.41-2.09 (m, 3H), 2.03-1.89 (m, 1H), 1.85-1.71 (m, 1H), 1.70-1.59 (m,6H), 1.59-1.37 (m, 9H), 1.37-1.27 (m, 3H), 1.25 (s, 3H), 1.22-1.04 (m,5H), 0.85 (s, 3H), 0.79 (t, J=7.6 Hz, 3H).

Synthesis of 3-7

To a solution of 3-6 (4.9 g, 14.8 mmol) in THE (50 mL) was added 9-BBNdimer (10.8 g, 44.4 mmol) at 15° C. After stirring at 40° C. for 1 h,ethanol (6.8 g, 148 mmol) was added at 15° C. followed by NaOH aqueous(29.5 mL, 5M, 148 mmol) and then H₂O₂ (14.7 mL, 10 M, 148 mmol) dropwiseat −10° C. After stirring at 80° C. for 1 h, the reaction mixture wasadded sat. Na₂S₂O₃ (50 mL). After stirring for 30 min, the mixture wasextracted with EtOAc (2×100 mL). The combined organic phase was washedwith saturated brine (2×100 mL), dried over anhydrous Na₂SO₄, andconcentrated under vacuum to give 3-7 (11 g). ¹H NMR (400 MHz, CDCl₃)δ_(H) 3.77-3.62 (m, 1H), 2.03-1.91 (m, 3H), 1.83-1.71 (m, 5H), 1.57-1.45(m, 12H), 1.24 (s, 3H), 1.21 (d, J=6.40 Hz, 3H), 1.18-0.94 (m, 7H),0.81-0.76 (m, 3H), 0.64 (s, 3H).

Synthesis of 3-8

To a solution of 3-7 (5.15 g, 14.8 mmol) in DCM (100 mL) was addedsilica gel (10 g) and PCC (6.36 g, 29.6 mmol) at 0° C. After stirring at15° C. for 3 h, the suspension was filtered, and the filter cake waswashed with DCM (2×100 mL). The combined filtrate was concentrated undervacuum to give a residue, which was purified by flash column(PE/EtOAc=20/1 to 4/1) to afford 3-8 (2.8 g, 54.6%). ¹H NMR (400 MHz,CDCl₃) δ_(H) 2.60-2.45 (m, 1H) 2.28-2.12 (m, 1 H), 2.11 (s, 3H),2.03-1.91 (m, 2H), 1.82-1.59 (m, 6H), 1.54-1.28 (m, 10H), 1.25 (s, 3H),1.24-1.03 (m, 6H), 0.79 (t, J=7.60 Hz, 3H), 0.59 (s, 3H).

Synthesis of 3-9

To a mixture of MePPh₃Br (4.5 g, 12.6 mmol) in THE (20 mL) was addedt-BuOK (1.41 g, 12.6 mmol) at 15° C. under N₂. After stirring at 50° C.for 30 min, 3-8 (2.2 g, 6.34 mmol) was added in portions below 50° C.After stirring at 50° C. for 1 h, the reaction mixture was quenched with10% NH₄Cl aqueous (100 mL) at 15° C. The organic layer was collected,and the aqueous layer was extracted with EtOAc (100 mL). The combinedorganic phase was concentrated under vacuum to give a residue, which waspurified by silica gel chromatography (PE/EtOAc=20/1 to 5/1) to afford3-9 (1.6 g, 73.3%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 4.84 (s, 1 H), 4.69(s, 1H), 2.04-1.90 (m, 2H), 1.87-1.76 (m, 2H), 1.75 (s, 3H), 1.73-1.57(m, 5H), 1.53-1.26 (m, 9H), 1.25 (s, 3H), 1.23-0.82 (m, 8H), 0.79 (t,J=7.60 Hz, 3H), 0.54 (s, 3H).

Synthesis of 3-10

To a solution of 3-9 (600 mg, 1.74 mmol) and NaHCO₃ (146 mg, 1.74 mmol)in DCM (30 mL) was added mCPBA (352 mg, 1.74 mmol) at 20° C. Afterstirring at 20° C. for 2 h, the mixture was quenched by saturated NaHCO₃aqueous (50 mL) at 20° C. The DCM phase was separated and washed withsaturated NaHCO₃/Na₂S₂O₃ aqueous (1:1, 2×100 mL), brine (100 mL), driedover Na₂SO₄, filtered and concentrated under vacuum to give 3-10 (600mg). ¹H NMR (400 MHz, CDCl₃) δ_(H) 2.88-2.30 (m, 2H), 2.08-1.60 (m, 9H),1.54-1.37 (m, 8H), 1.36-1.32 (m, 3H), 1.31-1.27 (m, 1H), 1.25 (s, 3H),1.23-0.97 (m, 8H), 0.83-0.74 (m, 4H), 0.66 (s, 2H).

Synthesis of 3 & 4

To a solution of 3-10 (600 mg, 1.66 mmol) in DMF (20 mL) was addedCs₂CO₃ (1.08 g, 3.32 mmol) and 1H-pyrazole-4-carbonitrile (230 mg, 2.48mmol). After stirring at 120° C. for 16 h, the mixture was added intosaturated NH₄Cl (100 mL). The organic layer was collected and theaqueous layer was extracted with EtOAc (3×100 mL). The combined organiclayer was washed with LiCl (100 mL, 5% in water), saturated brine (2×100mL), dried over anhydrous Na₂SO₄, filtered and concentrated to give amixture of 3 & 4 (800 mg).

The epimers (500 mg, 1.1 mmol) were separated by SFC (Column: DAICELCHIRALPAK AS (250 mm*30 mm, 10 um)), Condition: 0.1% NH₃ H₂O EtOH, BeginB: 30%, End B: 30%, FlowRate (ml/min): 80) to afford 3 (200 mg, 40%) and4 (150 mg, 30%).

3: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.92 (s, 1H), 7.82 (s, 1H), 4.34 (d,J=13.60 Hz, 1 H), 4.07 (d, J=13.60 Hz, 1H), 2.52 (s, 1H), 2.08-1.88 (m,2H), 1.83-1.59 (m, 6H), 1.55-1.45 (m, 3H), 1.44-1.27 (m, 8H), 1.25 (s,3H), 1.23-1.02 (m, 7H), 0.97 (s, 3H), 0.89 (s, 3H), 0.79 (t, J=7.60 Hz,3H). LC-ELSD/MS: purity >99%; analytic SFC:100% de; MS ESI calcd. forC₂₈H₄₀N₃[M−2H₂O+H]⁺ 418.3, found 418.3.

4: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.89 (s, 1H), 7.80 (s, 1H), 4.15 (d,J=14.0 Hz, 1 H), 4.00 (d, J=14.0 Hz, 1H), 2.31 (s, 1H), 2.10-1.84 (m,3H), 1.83-1.60 (m, 5H), 1.55-1.47 (m, 3H), 1.46-1.26 (m, 8H), 1.25 (s,3H), 1.24-1.09 (m, 7H), 1.08 (s, 3H), 0.85 (s, 3H), 0.79 (t, J=7.60 Hz,3H). LC-ELSD/MS: purity >99%; analytic SFC:99.18% de; MS ESI calcd. forC₂₈H₄₀N₃[M−2H₂O+H]⁺ 418.3, found 418.3.

EXAMPLE 5: Synthesis of1-((S)-2-((3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methoxypropyl)-1H-pyrazole-4-carbonitrile

To a solution of 3 (200 mg, 0.4408 mmol) in THE (5 mL) was added NaH(52.6 mg, 1.32 mmol, 60% in oil) at 0° C. After stirring for 20 min, MeI(93.8 mg, 0.6612 mmol) was added. After stirring at 25° C. for 16 h, thereaction mixture was diluted with H₂O (50 mL) and extracted with EtOAc(3×20 mL). The combined organic phase was washed with saturated brine(50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. Theresidue was purified by flash column (0-50% of EtOAc in PE) to giveproduct 5 (68.8 mg, 33.3%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.91 (s, 1H),7.75 (s, 1H), 4.30-4.15 (m, 2H), 3.18 (s, 3H), 2.00-1.88 (m, 2 H),1.81-1.71 (m, 2H), 1.66-1.60 (m, 3H), 1.54-1.47 (m, 3H), 1.47-1.26 (m,8H), 1.24 (s, 3H), 1.23-1.07 (m, 7H), 1.06 (s, 3H), 1.05-1.00 (m, 1H),0.86-0.75 (m, 6H). LC-ELSD/MS: purity >99%; analytic SFC:100% de; MS ESIcalcd. for C₂₈H₄₃N₃[M−2H₂O—CH₃+2H]+ 418.3, found 418.3.

EXAMPLE 6: Synthesis of1-((R)-2-((3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methoxypropyl)-1H-pyrazole-4-carbonitrile

To a solution of 4 (150 mg, 0.3306 mmol) in THE (5 mL) was added NaH(39.6 mg, 0.9918 mmol, 60% in oil) at 0° C. After stirring for 20 min,MeI (70.3 mg, 0.4959 mmol) was added. After stirring at 25° C. for 16 h,the reaction mixture was diluted with H₂O (50 mL) and extracted withEtOAc (3×20 mL). The combined organic phase was washed with saturatedbrine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated.The residue was purified by flash column (0-50% of EtOAc in PE) to giveproduct 6 (23.4 mg). ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.90 (s, 1H), 7.75(s, 1H), 4.23 (s, 2H), 3.14 (s, 3H), 2.12-1.91 (m, 2H), 1.80-1.61 (m,7H), 1.53-1.27 (m, 10H), 1.25 (s, 3H), 1.22-1.06 (m, 7H), 1.01 (s, 3H),0.82-0.77 (m, 6 H). LC-ELSD/MS: purity >99%; analytic SFC: 99.62% de; MSESI calcd. for C₂₈H₄₃N₃[M−2H₂O—CH₃+2H]⁺ 418.3, found 418.3.

EXAMPLES 7 & 8: Synthesis of1-((S)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-13-methyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile(7) &1-((R)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-13-methyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile(8)

Synthesis of 7-1

To a solution of 2,6-di-tert-butyl-4-methylphenol (13.1 g, 59.6 mmol) intoluene (20 mL) was added AlMe₃(14.9 mL, 29.8 mmol, 2 M in toluene)dropwise at 0° C. After stirring at 25° C. for 30 min, a solution of 7-0(3 g, 9.91 mmol) in anhydrous toluene (40 mL) was added dropwise at −70°C. After stirring at −70° C. for 1 h under N₂, n-PrMgCl (14.8 mL, 29.7mmol, 2 M in diethyl ether) was added dropwise at −70° C. After stirringat −70° C. for another 2 h, the reaction mixture was poured intosaturated aqueous citric acid (100 mL) below 10° C. and extracted withEtOAc (2×100 mL). The combined organic layer was dried over Na₂SO₄,filtered and concentrated in vacuum. The residue was purified by flashcolumn (0-10% of EtOAc in PE) to give 7-1 (1.7 g, 49%). ¹H NMR (400 MHz,CDCl₃) δ_(H) 2.53 (t, J=8 Hz, 1H), 2.16-2.11 (m, 4H), 2.04-1.98 (m, 1H),1.83-1.52 (m, 3H), 1.50-1.30 (m, 5H), 1.27-1.02 (m, 10H), 0.97-0.77 (m,11H), 0.61 (s, 3H).

Synthesis of 7-2

To a suspension of Ph₃PMeBr (3.50 g, 9.80 mmol) in THF (20 mL) was addedt-BuOK (1.09 g, 9.80 mmol). After stirring for 30 min at 16° C. underN₂, 7-1 (1.7 g, 4.90 mmol) was added. After stirring at 35° C. for 16 h,the reaction mixture was poured into water (300 mL) and extracted withEtOAc (3×100 mL). The combined organic phase was washed with brine (150mL), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by flash column (0˜5% of EtOAc in PE) to give 7-2 (1.3 g). ¹HNMR (400 MHz, CDCl₃) δ_(H) 4.84 (s, 1H), 4.70 (s, 1H), 2.06-2.01 (m,1H), 1.85-1.58 (m, 9H), 1.56-1.25 (m, 12H), 1.19-0.96 (m, 7H), 0.95-0.91(m, 3H), 0.9-0.83 (m, 3H), 0.57 (s, 3H).

Synthesis of 7-3

To a solution of 7-2 (1 g, 2.90 mmol) in DCM (10 mL) was added m-CPBA(1.17 g, 85%, 5.80 mmol) at 15° C. After stirring at 15° C. for 1 h, themixture was quenched by saturated NaHCO₃ aqueous (200 mL). The organicphase was separated and washed with saturated NaHCO₃/Na₂S₂O₃ aqueous(1:1, 3×100 mL), brine (100 mL), dried over Na₂SO₄, filtered andconcentrated under vacuum to give 7-3 (1 g). ¹H NMR (400 MHz, CDCl₃)δ_(H) 2.89 (d, J=4 Hz, 0.7H), 2.56-2.49 (m, 1H), 2.32 (d, J=4 Hz, 0.3H),2.04-1.51 (m, 10H), 1.48-1.23 (m, 15H), 1.21-0.99 (m, 6H), 0.95-0.91 (m,3H), 0.81-0.76 (m, 1H), 0.68 (s, 3H).

Synthesis of 7 & 8

To a solution of 7-3 (680 mg, 1.88 mmol) in DMF (10 mL) was added1H-pyrazole-4-carbonitrile (349 mg, 3.76 mmol) and Cs₂CO₃ (3.06 g, 9.40mmol). After stirring at 125° C. for 12 h, the reaction mixture wasdiluted with water (100 mL) and extracted with EtOAc (2×100 mL). Thecombined organic layer was separated, concentrated and purified by flashcolumn (0-20% EtOAc in PE) to give a mixture of epimers. The epimerswere separated by SFC (Column: DAICEL CHIRALPAK AS (250 mm*50 mm, 10um); Condition: 0.1% NH₃·H₂O EtOH; Begin B: 30; End B: 30; Flow Rate(mL/min): 200) to give 7 (250 mg) and 8 (104 mg).

7: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.93 (s, 1H), 7.81 (s, 1H), 4.36-4.33(m, 1H), 4.09-4.06 (m, 1H), 2.52 (s, 1H), 2.02-1.99 (m, 1H), 1.80-1.60(m, 8H), 1.56-1.41 (m, 5H), 1.40-1.03 (m, 15H), 0.97-0.91 (m, 9H).LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₈H₄₀N₃[M−2H₂O+H]⁺418.3, found418.3. SFC 99.9% de

8: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.89 (s, 1H), 7.80 (s, 1H), 4.17-4.14(m, 1H), 4.03-3.99 (m, 1H), 2.31 (s, 1H), 2.08-2.03 (m, 1H), 1.95-1.50(m, 10H), 1.47-1.18 (m, 13H), 1.16-1.00 (m, 8H), 0.95-0.87 (m, 6H).LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₈H₄₀N₃ [M−2H₂O+H]⁺418.3,found 418.3. SFC 98.22% de

EXAMPLES 9 & 10: Synthesis of1-((S)-2-hydroxy-2-((3R,5S,8R,9R,10S,13S,14S,17S)-3-hydroxy-13-methyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile(9) &1-((R)-2-hydroxy-2-((3R,5S,8R,9R,10S,13S,14S,17S)-3-hydroxy-13-methyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile(10)

Synthesis of 9-1

To the solution of 9-0 (15 g, 54.6 mmol) in THE (200 mL) was addedn-PrMgCl (81.5 mL, 163 mmol, 2M in THF) dropwise at −60° C. Afterstirring at −60° C. for 2 h, the reaction mixture was poured intosaturated aqueous NH₄Cl (100 mL) at 0° C. and extracted with EtOAc(2×200 mL). The combined organic layer was dried over Na₂SO₄, filteredand concentrated. The residue was triturated from MeCN (50 mL) at 80° C.to give 9-1 (7 g, 40.4%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 2.44 (dd, J=8.4,19.2 Hz, 1H), 2.14-2.00 (m, 1H), 1.99-1.84 (m, 2H), 1.83-1.71 (m, 3H),1.70-1.44 (m, 5H), 1.43-1.12 (m, 10H), 1.11-0.99 (m, 4H), 0.97-0.90 (m,3H), 0.88 (s, 3H), 0.81-0.66 (m, 2H).

Synthesis of 9-2

To a mixture of EtPPh₃Br (24.3 g, 65.6 mmol) in THF (80 mL) was addedt-BuOK (7.36 g, 65.6 mmol) at 15° C. under N₂. After stirring at 15° C.for 30 min, 9-1 (7 g, 21.9 mmol) in THF (20 mL) was added. Afterstirring at 40° C. for 1 h, the mixture was poured into NH₄Cl (50 mL)and the aqueous phase was extracted with EtOAc (2×100 mL). The combinedorganic phase was washed with brine (100 mL), dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was heated at 70° C. inMeOH (50 mL) for 30 minutes, cooled to room temperature, poured intowater (50 mL) and the resulting residue was filtered to give 9-2 (11 g).

¹H NMR (400 MHz, CDCl₃) δ_(H) 5.24-4.98 (m, 1H), 2.45-2.30 (m, 1H),2.28-2.11 (m, 2H), 1.88-1.74 (m, 2H), 1.73-1.57 (m, 7H), 1.55-1.48 (m,2H), 1.44-1.25 (m, 6H), 1.24-0.96 (m, 9H), 0.95-0.90 (m, 3H), 0.88 (s,3H), 0.78-0.62 (m, 2H).

Synthesis of 9-3

To a solution of 9-2 (6 g, 18.1 mmol) in anhydrous THE (60 mL) was added9-BBN dimer (13.2 g, 54.3 mmol) at 15° C. under N₂. After stirring at60° C. for 2 h, the mixture was cooled and quenched by EtOH (15 mL).NaOH (15 mL, 5M, 75.5 mmol) was added very slowly. After the addition,H₂O₂(22.6 mL, 226 mmol, 10 M) was added slowly below 30° C. Afterstirring at 60° C. for 2 h, the mixture was cooled, poured into water(50 mL) and extracted with EtOAc (2×50 mL). The combined organic layerwas dried over Na₂SO₄, filtered and concentrated in vacuum. The residuewas purified by column chromatography (20-25% of EtOAc in PE) to give9-3 (6.1 g, 52.8%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 3.86-3.57 (m, 1H),1.98-1.81 (m, 2H), 1.81-1.70 (m, 2H), 1.70-1.60 (m, 3H), 1.57-1.48 (m,3H), 1.42-1.25 (m, 7H), 1.23 (d, J=6.0 Hz, 3H), 1.17-0.96 (m, 9H),0.95-0.89 (m, 3H), 0.67 (s, 5H).

Synthesis of 9-4

To a solution of 9-3 (6.1 g, 17.5 mmol) in DCM (50 mL) was added PCC(11.2 g, 52.5 mmol) and silica gel (15 g) at 25° C. After stirring at25° C. for 1 h, the reaction mixture was filtered and the residue waswashed with anhydrous DCM (2×20 mL). The combined filtrate wasconcentrated in vacuum and then purified by column (15-20% of EtOAc inPE) to give 9-4 (3 g, 49.5%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 2.55 (t,J=8.8 Hz, 1H), 2.12 (s, 4H), 2.00 (td, J=3.2, 12.0 Hz, 1H), 1.89-1.73(m, 2H), 1.59 (br d, J=2.8 Hz, 1H), 1.55-1.50 (m, 1H), 1.49-1.16 (m,10H), 1.15-0.97 (m, 6H), 0.96-0.90 (m, 3H), 0.81-0.65 (m, 2H), 0.62 (s,3H).

Synthesis of 9-5

To a mixture of MePPh₃Br (9.25 g, 25.9 mmol) in THE (40 mL) was addedt-BuOK (2.9 g, 25.9 mmol) at 15° C. under N₂. After stirring at 15° C.for 30 min, 9-4 (3 g, 8.65 mmol) in THF (10 mL) was added. Afterstirring at 40° C. for 2 h, the mixture was poured into NH₄Cl.aq (150mL) and the aqueous phase was extracted with EtOAc (2×200 mL). Thecombined organic phase was washed with brine (20 mL), dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was heated inMeOH (500 mL) at 70° C. for 30 minutes, cooled to room temperature,added water (300 mL), filtered and dried to give 9-5 (3 g, 100%). ¹H NMR(400 MHz, CDCl₃) δ_(H) 4.85 (s, 1H), 4.71 (s, 1H), 2.11-1.98 (m, 1H),1.76 (s, 7H), 1.71-1.64 (m, 3H), 1.64-1.53 (m, 3H), 1.39 (d, J=3.6 Hz,4H), 1.14 (br s, 12H), 0.95-0.88 (m, 3H), 0.77-0.62 (m, 2H), 0.58 (s,3H).

Synthesis of 9-6

To a solution of 9-5 (1 g, 2.90 mmol) in DCM (10 mL) was added m-CPBA(750 mg, 4.35 mmol) at 20° C. After stirring at 20° C. for 2 h, themixture was poured into saturated NaHCO₃ aqueous (20 mL) and extractedwith EtOAc (2×50 mL). The combined organic solution was washed withsaturated NaHCO₃/Na₂S₂O₃ aqueous (1:1, 2×20 mL), brine (20 mL), driedover Na₂SO₄, filtered and concentrated to give 9-6 (1.5 g). ¹H NMR (400MHz, CDCl₃) δ_(H) 2.89 (d, J=4.4 Hz, 1H), 2.58-2.54 (m, 1H), 2.04-1.86(m, 2H), 1.81-1.72 (m, 3H), 1.66-1.50 (m, 8H), 1.39-1.37 (m, 6H), 1.35(s, 3H), 1.31-1.16 (m, 5H), 1.15-1.05 (m, 7H), 1.04-0.94 (m, 5H),0.93-0.89 (m, 5H), 0.68 (s, 3H).

Synthesis of 9 & 10

To a solution of 9-6 (750 mg, 2.07 mmol) in DMF (10 mL) was added1H-pyrazole-4-carbonitrile (481 mg, 5.17 mmol) and Cs₂CO₃ (3.35 g, 10.3mmol). After stirring at 130° C. for 16 h, the reaction mixture wasdiluted with water (20 mL) and extracted with EtOAc (2×30 mL). Thecombined organic phase was washed with brine (20 mL), dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was purified byflash column (0-20% EtOAc in PE) to give a mixture of epimers (600 mg,63.8%) which were separated SFC (Column: DAICEL CHIRALPAK AS 250 mm×30mm, 10 um; Condition: 0.1% NH₃H₂O EtOH; Gradient: from 25% to 25% of B;Flow rate: 70 mL/min; Column temperature: 40° C.) to afford 9 (230 mg)and 10 (86.9 mg). 9 (230 mg) was triturated from MeCN (5 mL) at 20° C.to give 9 (193.3 mg).

9: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.92 (s, 1H), 7.81 (s, 1H), 4.36 (d,J=14.0 Hz, 1H), 4.08 (d, J=14.0 Hz, 1H), 2.49 (s, 1H), 2.04-1.96 (m,1H), 1.78-1.57 (m, 8H), 1.54-1.49 (m, 1H), 1.45-1.41 (m, 1H), 1.38 (brd, J=3.2 Hz, 4H), 1.34-1.12 (m, 5H), 1.12-1.02 (m, 5H), 1.01-0.94 (m,5H), 0.92 (s, 6H), 0.71-0.62 (m, 2H). LC-ELSD/MS purity 99%, MS ESIcalcd. for C₂₈H₄₀N₃[M−2H₂O+H]⁺418.3 found 418.3. SFC 99% de.

10: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.89 (s, 1H), 7.80 (s, 1H), 4.19-4.12(m, 1H), 4.04-3.98 (m, 1H), 2.27 (s, 1H), 2.07-2.01 (m, 1H), 1.91 (q,J=10.4 Hz, 1H), 1.75 (br d, J=13.2 Hz, 2H), 1.70-1.57 (m, 5H), 1.52-1.45(m, 2H), 1.38 (br d, J=3.2 Hz, 4H), 1.35-1.12 (m, 6H), 1.11-1.08 (m,5H), 1.05-0.90 (m, 7H), 0.88 (s, 3H), 0.72-0.63 (m, 2H). LC-ELSD/MSpurity 99%, MS ESI calcd. for C₂₈H₄₀N₃[M−2H₂O+H]⁺418.3 found 418.3. SFC99% de.

EXAMPLES 11 & 12: Synthesis of1-((S)-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-ethyl-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile(11) &1-((R)-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-ethyl-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile(12)

Synthesis of 11-1

To a solution of BHT (12 g, 54.4 mmol) in toluene (120 mL) undernitrogen at 0° C. was added trimethylaluminum (2 M in toluene, 14 mL, 28mmol) dropwise. After stirring at 25° C. for 1 h, to the MAD solutionwas added a solution of 7-0 (6 g, 19.8 mmol) in DCM (60 mL) dropwise at−70° C. After stirring at −70° C. for 1 h under N₂, EtMgBr (20 mL, 60mmol, 3M in ethyl ether) was added dropwise at −70° C. After stirring at−70° C. for 1 h, the reaction mixture was poured into saturated aqueouscitric acid (600 mL) below 10° C. and extracted with DCM (2×800 mL). Thecombined organic layer was dried over Na₂SO₄, filtered and concentrated.The residue was triturated by PE to give 11-1 (3.83 g, 58%). ¹H NMR (400MHz, CDCl₃) δ_(H) 2.56-2.50 (m, 1H), 2.24-2.10 (m, 4H), 2.07-1.99 (m,1H), 1.89-1.51 (m, 9H), 1.50-1.20 (m, 12H), 1.19-1.00 (m, 3H), 0.98-0.80(m, 3H), 0.61 (s, 3H).

Synthesis of 11-2

To a suspension of MePh₃PBr (6.4 g, 18.0 mmol) in THE (50 mL) was addedt-BuOK (2.01 g, 18.0 mmol). After stirring at 40° C. for 10 min, themixture was slowly added dropwise to a solution of 11-1 (3 g, 9.02 mmol)in THE (30 mL). After stirring at 20° C. for 18 h, the mixture wasquenched with sat. NH₄Cl (100 mL) and extracted with EtOAc (3×100 mL).The combined organic phase was washed with sat. NH₄Cl (100 mL), driedover Na₂SO₄, filtered, and concentrated. The residue was purified bycombi-flash (0-25% of EtOAc in PE) to give 11-2 (2.445 g, 82%). ¹H NMR(400 MHz, CDCl₃) δ_(H) 4.84 (s, 1H), 4.69 (s, 1H), 2.02-1.53 (m, 13H),1.50-1.33 (m, 4H), 1.32-1.11 (m, 11H), 1.10-0.99 (m, 2H), 0.85-0.80 (m,3H), 0.56 (s, 3H).

Synthesis of 11-3

To a solution of 11-2 (1.8 g, 5.44 mmol) in DCM (20 mL) was added m-CPBA(2.18 g, 85%, 10.8 mmol). After stirring at 15° C. for 1 h, the mixturewas quenched by NaHCO₃ (50 mL, sat. aq.) and Na₂S₂O₃ (20 mL, sat. aq.).The organic layer was separated, dried over Na₂SO₄, filtered andconcentrated in vacuum to give 11-3 (1.7 g), which was used as is.

Synthesis of 11 & 12

To a solution of 11-3 (850 mg, 2.45 mmol) in DMF (10 mL) was added1H-pyrazole-4-carbonitrile (341 mg, 3.67 mmol) and Cs₂CO₃ (3.97 g, 12.2mmol) at 20° C. After stirring at 120° C. for 2 h, the reaction mixturewas diluted with water (100 mL) and extracted with EtOAc (2×50 mL). Thecombined organic layer was separated, concentrated and purified by flashcolumn (30˜65% EtOAc in PE) to give a mixture of epimers. The epimerswere separated by SFC (Column DAICEL CHIRALPAK AS (250 mm*30 mm, 10 um)Condition 0.1% NH₃H₂O EtOH Begin B 25% End B 25% Gradient Time(min) 100%B Hold Time(min) FlowRate (ml/min) 70) to give 11 (395.8 mg, 49.6%) and12 (155.4 mg, 19.4%).

11: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.93 (s, 1H), 7.82 (s, 1H), 4.45-3.99(m, 2H), 2.50 (br s, 1H), 2.08-1.94 (m, 1H), 1.84-1.57 (m, 10H),1.47-1.02 (m, 16H), 0.97 (s, 3H), 0.92 (s, 3H), 0.88 (t, J=7.5 Hz, 3H).LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₇H₃₈N₃ [M−2H₂O+H]⁺404.3,found 404.3. SFC 100% de

12: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.90 (br s, 1H), 7.81 (s, 1H),4.24-3.90 (m, 2H), 2.29 (br s, 1H), 2.06 (br d, J=12.3 Hz, 1H),1.96-1.86 (m, 1H), 1.84-1.56 (m, 9H), 1.53-1.19 (m, 12H), 1.19-1.09 (m,7H), 0.92-0.85 (m, 6H). LC-ELSD/MS purity 99%, MS ESI calcd. forC₂₇H₃₈N₃ [M−2H₂O+H]⁺ 404.3, found 404.3. SFC 99% de.

Examples 13 & 14: Synthesis of1-((S)-2-((3R,5S,8R,9R,10S,13S,14S,17S)-3-ethyl-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile(13) &1-((R)-2-((3R,5S,8R,9R,10S,13S,14S,17S)-3-ethyl-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile(14)

Synthesis of 13-1

Lithium (7.27 g, 915 mmol) was added to fresh prepared liquid ammonia(500 mL) in portions at −70° C. After stirring at −70° C. for 1 hour, asolution of 13-0 (50 g, 183 mmol) in dry THF (500 mL) and t-butanol (27g, 366 mmol) were added. After stirring at −70° C. for 1 h, ammoniumchloride (500 g) was added and allowed to warm to room temperature.After stirring for 16 h, the reaction mixture was diluted with H₂O (1 L)and extracted with EtOAc (3×500 mL). The combined organic solution waswashed with HCl (1 M, 2×500 mL), saturated NaHCO₃ aqueous (500 mL),brine (1 L), dried over Na₂SO₄ and concentrated under vacuum to give13-1 (97 g). ¹H NMR (400 MHz, CDCl₃) δ_(H) 3.75-3.55 (m, 1H), 2.50-2.00(m, 10H), 2.00-1.25 (m, 8H), 1.25-0.60 (in, 9H).

Synthesis of 13-2

To a solution of 13-1 (100 g, 361 mmol) in DCM (1000 mL) at 0° C. wasadded silica gel (116 g) and PCC (116 g, 541 mmol). After stirring at25° C. for 2 h, the reaction mixture was diluted with PE (1000 mL) andfiltered through a pad of silica gel. The filter cake was washed withDCM (2000 mL). The combined filtrate was concentrated to give 13-2 (90g). ¹H NMR (400 MHz, CDCl₃) δ_(H) 2.55-2.02 (m, 8H), 2.02-1.39 (m, 8H),1.39-0.69 (m, 10H).

Synthesis of 13-3

To a solution of 13-2 (51.5 g, 187 mmol) in MeOH (600 mL) was added4-methylbenzenesulfonic acid (6.44 g, 37.4 mmol) at 25° C. Afterstirring at 55° C. for 16 h, Et₃N (20 mL) was added and the mixture wasfiltered to afford 13-3 (57 g). ¹H NMR (400 MHz, CDCl₃) δ_(H) 3.49 (d,J=5.6 Hz, 1H), 3.20 (s, 3H), 3.14 (s, 3H), 2.48-2.38 (m, 1H), 2.12-2.01(m, 2H), 1.96-1.90 (m, 2H), 1.88-1.74 (m, 4H), 1.68-1.62 (m, 1H),1.56-1.44 (m, 1H), 1.35-1.20 (m, 5H), 1.13-0.95 (m, 5H), 0.87 (s, 1H),0.80-0.68 (m, 2H).

Synthesis of 13-4

To a mixture of EtPPh₃Br (98.7 g, 266 mmol) in THE (250 mL) was addedt-BuOK (29.8 g, 266 mmol) at 15° C. under N₂. After stirring at 15° C.for 30 min, 13-3 (28.5 g, 88.9 mmol) in THE (50 mL) was added. Afterstirring at 40° C. for 2 h, the mixture was poured into NH₄Cl.aq (150mL) and extracted with EtOAc (2×200 mL). The combined organic phase waswashed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was heated in MeOH (500 mL) at 70° C. for 30min, cooled to room temperature, diluted with water (300 mL), filteredand concentrated to give 13-4 (25.5 g). ¹H NMR (400 MHz, CDCl₃) δ_(H)5.15-5.07 (m, 1H), 3.20 (s, 3H), 3.14 (s, 3H), 2.41-2.31 (m, 1H),2.27-2.12 (m, 2H), 2.10-2.02 (m, 1H), 1.91 (td, J=3.2, 13.2 Hz, 1H),1.85-1.76 (m, 2H), 1.71-1.58 (m, 6H), 1.57-1.48 (m, 3H), 1.30-1.13 (,m,6H), 1.11-0.93 (m, 5H), 0.87 (s, 3H), 0.75-0.67 (m, 2H).

Synthesis of 13-5

To a solution of 13-4 (51 g, 153 mmol) in THE (500 mL) was added 1 M HCl(153 mL, 153 mmol). After stirring stirred at 15° C. for 2 h, themixture was poured into NaHCO₃.aq (400 mL). and extracted with EtOAc(2×300 mL). The combined organic phase was washed with brine (200 mL),dried over anhydrous Na₂SO₄, filtered and concentrated to give 13-5 (42g, 95.8%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 5.16-5.08 (m, 1H), 2.42-2.17(m, 7H), 2.09 (t, J=13.2 Hz, 1H), 1.88-1.79 (m, 2H), 1.76-1.63 (m, 6H),1.59 (s, 1H), 1.56-1.40 (m, 2H), 1.28-1.16 (m, 8H), 1.04-0.94 (m, 1H),0.90 (s, 1H), 0.78-0.69 (m, 1H).

Synthesis of 13-6

To a stirred solution of Me₃SIO (47.9 g, 218 mmol) in DMSO (300 mL) andTHE (300 mL) was added NaH (5.23 g, 218 mmol) at 0° C. After stirringfor 1 h under N₂., 13-5 (42 g, 146 mmol) in THE (200 mL) was added.After stirring at 25° C. for 3 h, the reaction mixture was poured intowater (1000 mL). After stirring at 25° C. for 3 h, the mixture wasfiltered to give 13-6 (48 g). ¹H NMR (400 MHz, CDCl₃) δ_(H) 5.15-5.07(m, 1H), 2.64-2.61 (m, 5H), 2.41-2.30 (m, 1H), 2.27-2.11 (m, 2H),2.00-1.92 (m, 1H), 1.91-1.80 (m, 2H), 1.67-1.60 (m, 5H), 1.56-1.50 (m,1H), 1.45-1.35 (m, 1H), 1.30-1.10 (m, 8H), 1.07-0.95 (m, 2H), 0.89 (s,3H), 0.84-0.72 (m, 2H).

Synthesis of 13-7

To a suspension of CuCN (3.92 g, 43.8 mmol) in THE (40 mL) at −70° C.was added MeLi (54.7 mL, 87.6 mmol, 1.6M). After stirring at −70° C. for1 h, 13-6 (4.4 g, 14.6 mmol) in THF (10 mL) was added at −70° C. Afterslowly warming to rt and stirring for 2 h, the reaction was slowlypoured into 10% NH₄Cl (20 mL) and extracted with EtOAc (2×50 mL). Thecombined organic phase was washed with brine (20 mL), dried overanhydrous Na₂SO₄, filtered and concentrated to give 13-7 (4.4 g). ¹H NMR(400 MHz, CDCl₃) δ_(H) 5.14-5.08 (m, 1H), 2.39-2.10 (m, 3H), 1.85-1.39(m, 10H), 1.39-0.94 (m, 13H), 0.94-0.60 (m, 9H).

Synthesis of 13-8

To a solution of 13-7 (4.4 g, 13.3 mmol) in anhydrous THE (50 mL) wasadded 9-BBN dimer (8.03 g, 33.2 mmol) at 25° C. under N₂. After stirringat 60° C. for 16 h, the mixture was cooled, and diluted by EtOH (20 mL)at 0° C. NaOH (2.66 g, 13.3 mL, 5M, 66.5 mmol) was added very slowlyfollowed by H₂O₂(13.3 mL, 133 mmol, 10 M in water) very slowly until theinner temperature no longer rises and the inner temperature wasmaintained below 30° C. After stirring at 60° C. for 2 h, the mixturewas cooled, diluted with Na₂S₂O₃ (100 mL, sat. aq.) and extracted withEtOAc (3×100 mL). The combined organic layer was dried over Na₂SO₄,filtered and concentrated in vacuum. The residue was purified by column(5%-30% of EtOAc in PE) to give 13-8 (10 g). ¹H NMR (400 MHz, CDCl₃)δ_(H) 3.74-3.66 (m, 1H), 1.96-1.39 (m, 13H), 1.39-1.00 (m, 14H),1.00-0.85 (m, 5H), 0.75-0.57 (m, 5H).

Synthesis of 13-9

To a solution of 13-8 (1.3 g, 3.88 mmol) in DCM (20 mL) was added DMP(3.29 g, 7.76 mmol). After stirring at 25° C. for 1 h, the mixture wasquenched with NaHCO₃ (50 mL) and extracted with EtOAc (3×30 mL). Thecombined organic layer was washed with Na₂S₂O₃ (3×30 mL, sat.), brine(50 mL), dried over Na₂SO₄, filtered and concentrated in vacuum. Theresidue was purified by column (5%-30% of EtOAc in PE) to give to give13-9 (1.16 g, 90%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 2.53 (t, J=8.8 Hz,1H), 2.21-1.53 (m, 9H), 1.53-1.10 (m, 10H), 1.10-0.63 (m, 13H), 0.61 (s,3H).

Synthesis of 13-10

To a mixture of MePPh₃Br (2.48 g, 6.96 mmol) in THE (40 mL) was addedt-BuOK (779 mg, 6.96 mmol) at 25° C. under N₂. After stirring at 50° C.for 30 mins. 13-9 (1.16 g, 3.48 mmol) in THE (10 mL) was added at 25° C.After stirring at 50° C. for 18 h, the reaction mixture was quenchedwith water (40 mL) at 25° C. and extracted with EtOAc (2×50 mL). Thecombined organic phase was washed with water (3×10 mL), brine (30 mL),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum. Theresidue was purified by column (2% of EtOAc in PE) to give 13-10 (620mg, 54%). ¹H NMR (400 MHz, CDCl3) δ_(H) 4.84 (s, 1H), 4.70 (s, 1H),2.08-1.57 (m, 10H), 1.57-1.06 (m, 13H), 1.06-0.52 (m, 13H).

Synthesis of 13-11

To a solution of 13-10 (620 mg, 1.87 mmol) in DCM (10 mL) was addedm-CPBA (601 mg, 2.8 mmol, 80%) at 15° C. After stirring at 15° C. for 1h, the mixture was quenched with sat.NaHCO₃ and Na₂S₂O₃ (40 mL, v:v=1:1)and extracted with DCM (2×20 mL). The combined organic phase was washedwith sat. NaHCO₃ and Na₂S₂O₃ (50 mL, v:v=1:1), dried over Na₂SO₄,filtered and concentrated to give 13-11 (820 mg). ¹H NMR (400 MHz,CDCl₃) δ_(H) 2.89 (d, J=4.8 Hz, 0.6H), 2.55-2.48 (m, 1H), 2.32 (d, J=5.2Hz, 0.4H), 2.02-1.45 (m, 10H), 1.45-1.11 (m, 11H), 1.11-0.74 (m, 10H),0.74-0.58 (m, 5H).

Synthesis of 13 & 14

To a solution of 13-11 (800 mg, 2.3 mmol) in DMF (10 mL) were addedCs₂CO₃ (2.24 g, 6.89 mmol) and 1H-pyrazole-4-carbonitrile (535 mg, 5.75mmol). After stirring at 120° C. for 48 h, the reaction mixture wasadded into saturated NH₄Cl (50 mL) and extracted with EtOAc (3×50 mL).The combined organic layer was washed with LiCl (100 mL, 5% in water),saturated brine (2×100 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by column (0˜10% of EtOAc in PE)to afford a mixture of epimers (800 mg). The epimers were separated bySFC (Column: DAICEL CHIRALCEL OJ-H (250 mm*30 mm, 5 um), Condition:0.10% % NH₃H₂O EtOH, Begin B: 25%, End B: 25%) to give 13 (264 mg) and14 (122 mg).

13: ¹H NMR (400 MHz, CDCl3) δ_(H) 7.92 (s, 1H), 7.81 (s, 1H), 4.37-4.33(m, 1H), 4.10-4.06 (m, 1H), 2.48 (s, 1H), 2.02-1.96 (m, 1H), 1.79-1.37(m, 12H), 1.37-0.94 (m, 15H), 0.94-0.87 (m, 6H), 0.75-0.61 (m, 2H).LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₇H₃₈N₃ [M−2H₂O+H]⁺404found404. SFC 99.522% de.

14: ¹H NMR (400 MHz, CDCl3) δ_(H) 7.92 (s, 1H), 7.79 (s, 1H), 4.17-4.13(m, 1H), 4.02-3.99 (m, 1H), 2.27 (s, 1H), 2.07-1.53 (m, 1H), 1.53-1.12(m, 12H), 1.12-0.94 (m, 15H), 0.94-0.84 (m, 6H), 0.73-0.61 (m, 2H).LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₇H₃₈N₃ [M−2H₂O+H]⁺404found404. SFC100% de.

Examples 15 & 16: Synthesis of1-((S)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3-(hydroxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile(15) &1-((R)-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-(ethoxymethyl)-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile(16)

Synthesis of 15-1

To a solution of MePPh₃Br (2.94 g, 8.25 mmol) in THE (20 mL) was addedt-BuOK (925 mg, 8.25 mmol) under N₂ at 25° C. After stirring for 1 h,15-0 (1 g, 2.75 mmol, WO 2018013613) in THE (10 mL) was added. Afterstirring at 40° C. for 3 h, the reaction mixture was poured intoNH₄Cl.aq (50 mL) and extracted with EtOAc (2×80 mL). The combinedorganic phase was washed with saturated brine (50 mL), dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was purified byflash column (0-6% of EtOAc in PE) to give 15-1 (750 mg, 76%). ¹H NMR(400 MHz, CDCl3) δ_(H) 4.84 (s, 1H), 4.70 (s, 1H), 3.57-3.49 (m, 2H),3.47-3.38 (m, 2H), 2.70 (s, 1H), 2.07-2.00 (m, 1H), 1.75 (s, 7H),1.72-1.59 (m, 5H), 1.49-1.33 (m, 6H), 1.28-0.97 (m, 11H), 0.56 (s, 3H).

Synthesis of 15-2

To a solution of 15-1 (880 mg, 2.44 mmol) in DCM (20 mL) was addedm-CPBA (990 mg, 85%, 4.88 mmol) at 15° C. After the reaction mixture wasstirred at 15° C. for 1 h, the reaction mixture was quenched bysaturated NaHCO₃ aqueous (200 mL). The organic phase was separated andwashed with saturated NaHCO₃/Na₂S₂O₃ aqueous (1:1, 3×100 mL), brine (100mL), dried over Na₂SO₄, filtered and concentrated under vacuum to give15-2 (900 mg). ¹H NMR (400 MHz, CDCl₃) δ_(H) 3.54 (q, J=8 Hz, 2H), 3.43(q, J=8 Hz, 2H), 2.88 (d, J=4 Hz, 0.6H), 2.55 (d, J=4 Hz, 0.7H), 2.49(d, J=4 Hz, 0.3H), 2.31 (d, J=4 Hz, 0.4H), 2.03-1.57 (m, 10H), 1.48-1.32(m, 9H), 1.28-0.93 (m, 12H), 0.79 (s, 1H), 0.67 (s, 2H).

Synthesis of 15 & 16

To a solution of 15-2 (600 mg, 1.59 mmol) in DMF (5 mL) were added1H-pyrazole-4-carbonitrile (369 mg, 3.97 mmol) and Cs₂CO₃ (2.59 g, 7.95mmol). After stirring at 125° C. for 12 h, the reaction mixture wasdiluted with water (100 mL) and extracted with EtOAc (3×60 mL). Thecombined organic layer was washed with LiCl (3×150 mL, 5%, aq.) and thenconcentrated. The residue was purified by flash column (0˜20% of EtOAcin PE) to give a mixture of epimers (600 mg). The epimers were separatedby SFC (Column: DAICEL CHIRALPAK AS (250 mm*50 mm, 10 um); Condition:0.1% NH₃H₂O EtOH; Begin B: 60%; End B: 60%; Flow Rate (ml/min): 80) togive 15 (353.8 mg, 59%) and 16 (138.3 mg, 23%).

15: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.92 (s, 1H), 7.82 (s, 1H), 4.37-4.34(m, 1H), 4.10-4.07 (m, 1H), 3.54 (q, J=8 Hz, 2H), 3.41 (q, J=8 Hz, 2H),2.70 (s, 1H), 2.51 (s, 1H), 2.02-1.99 (m, 1H), 1.83-1.55 (m, 8H),1.50-1.19 (m, 13H), 1.15-1.02 (m, 5H), 0.96-0.91 (m, 6H). LC-ELSD/MSpurity 99%, MS ESI calcd. for C₂₈H₄₂N₃O₂[M+H-H₂O]⁺ 452, found 452. SFC100% de.

16: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.89 (s, 1H), 7.80 (s, 1H), 4.18-4.15(m, 1H), 4.03-3.99 (m, 1H), 3.54 (q, J=8 Hz, 2H), 3.41 (q, J=8 Hz, 2H),2.71 (s, 1H), 2.33 (s, 1H), 2.07-2.04 (m, 1H), 1.95-1.56 (m, 9H),1.50-1.19 (m, 13H), 1.16-1.00 (m, 8H), 0.87 (s, 3H). LC-ELSD/MS purity99%, MS ESI calcd. for C₂₈H₄₂N₃O₂[M+H-H₂O]⁺ 452, found 452. SFC 99.94%de.

Examples 17 & 18: Synthesis of1-((S)-2-hydroxy-2-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-10,13-dimethyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile(17) &1-((R)-2-hydroxy-2-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-10,13-dimethyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile(18)

Synthesis of 17-1

To a stirred solution of Me₃SIO (3.12 g, 14.2 mmol) in DMSO (30 mL) andTHE (30 mL) was added NaH (340 mg, 14.2 mmol) at 0° C. After stirringfor 1 h, the reaction mixture was added 17-0 (Pregn-20-en-3-one,20-methyl-, (5α)-, described in WO2018/75699) (3 g, 9.53 mmol) in DMSO(30 mL). After stirring at 25° C. for 3 h, the reaction mixture waspoured into water (200 mL). After stirring at 25° C. for 3 h, thereaction mixture was filtered to give 17-1 (3.3 g). ¹H NMR (400 MHz,CDCl₃) δ_(H) 4.84 (s, 1H), 4.70 (s, 1H), 2.64-2.59 (m, 2H), 2.06-1.98(m, 2H), 1.88-1.79 (m, 2H), 1.75 (s, 3H), 1.71-1.65 (m, 3H), 1.60-1.52(m, 3H), 1.35-1.12 (m, 8H), 1.00-0.76 (m, 8H), 0.57 (s, 3H).

Synthesis of 17-2

To a solution of 17-1 (2.7 g, 8.21 mmol) in THE (20 mL) with CuI (234mg, 1.23 mmol) at 0° C. was added EtMgBr (8.20 mL, 3 M, 24.6 mmol).After stirring at 0° C. for 1 h, the reaction was diluted with water (50mL) and extracted with EtOAc (2×50 mL). The combined organic phase waswashed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by column (0˜3% of EtOAc in PE)to give 17-2 (1.8 g, 61%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 4.83 (s, 1H),4.69 (s, 1H), 2.01 (t, J=9.2 Hz, 1H), 1.83-1.40 (m, 13H), 1.40-1.02 (m,15H), 1.02-0.70 (m, 8H), 0.55 (s, 3H).

Synthesis of 17-3

To a solution of 17-2 (1.7 g, 4.74 mmol) in DCM (10 mL) was added m-CPBA(2.03 g, 9.48 mmol, 80%) at 15° C. After stirring at 15° C. for 1 h, themixture was quenched with sat.NaHCO₃ and Na₂S₂O₃ (40 mL, v:v=1:1) andextracted with DCM (2×20 mL). The combined organic phase was washed withsat. NaHCO₃ and Na₂S₂O₃ (50 mL, v:v=1:1), dried over Na₂SO₄, filteredand concentrated to give 17-3 (2.35 g). ¹H NMR (400 MHz, CDCl₃) δ_(H)2.88 (d, J=4.4 Hz, 0.7H), 2.55-2.48 (m, 1H), 2.30 (d, J=4.8 Hz, 0.3H),2.04-1.55 (m, 10H), 1.55-1.37 (m, 10H), 1.37-1.23(m, 10H), 1.23-0.66 (m,10H),

Synthesis of 17 & 18

To a solution of 17-3 (600 mg, 1.6 mmol) in DMF (5 mL) were added Cs₂CO₃(1.56 g, 4.8 mmol) and 1H-pyrazole-4-carbonitrile (372 mg, 4 mmol).After stirring at 120° C. for 48 h, the reaction mixture was added intosaturated NH₄Cl (50 mL) and extracted with EtOAc (3×50 mL). The combinedorganic layer was washed with LiCl (100 mL, 5% in water), brine (2×100mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residuewas purified by column (5˜20% of EtOAc in PE) to afford a mixture ofepimers (750 mg). The epimers were separated by SFC (Column: DAICELCHIRALCEL OJ-H (250 mm*30 mm, 5 um), Condition: 0.1% NH₃H₂O EtOH, BeginB: 30%, End B: 30%) to give 17 (272 mg) and 18 (123 mg).

17: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.92 (s, 1H), 7.80 (s, 1H), 4.36-4.33(m, 1H), 4.09-4.06 (m, 1H), 2.49 (s, 1H), 2.01-1.98 (m, 1H), 1.77-1.42(m, 11H), 1.42-1.08 (m, 13H), 1.08-0.80 (m, 11H), 0.77-0.70 (m, 4H).LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₉H₄₂N₃ [M−2H₂O+H]⁺432found432. SFC 99.06% de.

18: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.88 (s, 1H), 7.79 (s, 1H), 4.17-4.13(m, 1H), 4.02-3.98 (m, 1H), 2.28 (s, 1H), 2.06-1.86 (m, 2H), 1.71-1.42(m, 10H), 1.42-1.11 (m, 13H), 1.11-0.60 (m, 11H), 0.77-0.70 (m, 4H).LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₉H₄₂N₃ [M−2H₂O+H]⁺432found432. SFC 100% de.

Examples 19 & 20: Synthesis of1-((S)-2-hydroxy-2-((3R,5S,8R,9R,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile(19) &1-((R)-2-hydroxy-2-((3R,5S,8R,9R,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile(20)

Synthesis of 19-1

To a mixture of MePPh₃Br (4.28 g, 12.0 mmol) in THE (15 mL) was addedt-BuOK (1.34 g, 12.0 mmol) at 25° C. under N₂. After stirring at 50° C.for 30 min, 19-0 (1.4 g, 4.01 mmol) in THE (5 mL) was added. Afterstirring at 60° C. for 3 h, the reaction mixture was cooled, poured toice water, and with EtOAc (100 mL×2). The combined organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated. Theresidue was purified by flash column (0˜30% of EtOAc in PE) to give 19-1(1.1 g). ¹H NMR (400 MHz, CDCl₃) δ_(H) 4.94-4.61 (m, 2H), 3.45-3.32 (m,3H), 3.25-3.12 (m, 2H), 2.11-1.97 (m, 2H), 1.87-1.53 (m, 10H), 1.49-0.82(m, 14H), 0.79-0.65 (m, 2H), 0.57 (s, 3H).

Synthesis of 19-2

To a solution of 19-1 (600 mg, 1.73 mmol) in DCM (20 mL) was addedm-CPBA (556 mg, 2.59 mmol, 80%) at 15° C. After stirring at 15° C. for 1h, the reaction mixture was quenched with sat. NaHCO₃ and Na₂S₂O₃ (40mL, v:v=1:1) and extracted with DCM (2×20 mL). The combined organicphase was washed with sat. NaHCO₃ and Na₂S₂O₃ (50 mL, v:v=1:1), driedover Na₂SO₄, filtered and concentrated to give 19-2 (650 mg). ¹H NMR(400 MHz, CDCl₃) δ_(H) 3.38 (s, 3H), 3.24-3.14 (m, 2H), 2.88 (d, J=4.4Hz, 1H), 2.55 (d, J=4.4 Hz, 1H), 2.49 (d, J=4.8 Hz, 1H), 2.31 (d, J=4.8Hz, 1H), 2.09-1.52 (m, 10H), 1.47-0.87 (m, 14H), 0.80 (s, 1H), 0.74-0.64(m, 4H).

Synthesis of 19 & 20

To a solution of 19-2 (650 mg, 1.79 mmol) in DMF (10 mL) were addedCs₂CO₃ (1.75 g, 5.37 mmol) and 1H-pyrazole-4-carbonitrile (416 mg, 4.47mmol). After stirring at 130° C. for 12 h, the reaction mixture wasadded into saturated NH₄Cl (50 mL) and extracted with EtOAc (3×50 mL).The combined organic layer was washed with LiCl (100 mL, 5% in water),brine (2×100 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by column (0˜50% of EtOAc in PE)to afford a mixture of epimers (750 mg). The epimers were separated bySFC (Column: DAICEL CHIRALCEL OJ-H (250 mm*30 mm, 5 um); Condition: 0.1%NH₃H₂O EtOH) to afford 20 (116.0 mg, 15.5%) and 19 (280.6 mg, 37.4%).

19: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.92 (s, 1H), 7.81 (s, 1H), 4.36 (d,J=13.6 Hz, 1H), 4.08 (d, J=13.6 Hz, 1H), 3.38 (s, 3H), 3.18 (s, 2H),2.48 (s, 1H), 2.13-1.92 (m, 2H), 1.81-1.56 (m, 9H), 1.43 (br t, J=9.6Hz, 2H), 1.29-0.98 (m, 9H), 0.96 (s, 4H), 0.92 (s, 3H), 0.69 (br s, 2H).LC-ELSD/MS purity 99%, MS ESI calcd for C₂₆H₃₅N₃[M-MeOH−2H₂O+H]⁺ 388.2,found 388.2. SFC 96.66% de

20: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.89 (s, 1H), 7.82-7.75 (m, 1H),4.22-4.09 (m, 1H), 4.06-3.93 (m, 1H), 3.48-3.31 (m, 3H), 3.27-3.11 (m,2H), 2.35-2.22 (m, 1H), 2.12-1.99 (m, 2H), 1.97-1.83 (m, 1H), 1.81-1.60(m, 8H), 1.53-1.32 (m, 2H), 1.29-1.14 (m, 4H), 1.09 (s, 5H), 1.05-0.92(m, 4H), 0.87 (s, 3H), 0.69 (br t, J=7.2 Hz, 2H). LC-ELSD/MS purity 99%,MS ESI calcd for C₂₆H₃₅N₃[M-MeOH−2H₂O+H]⁺ 388.2, found 388.2. SFC 100%de

Example 21: Synthesis of1-(2,2-difluoro-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl)-1H-pyrazole-4-carbonitrile

Synthesis of 21-1

To a solution of 21-0 (1 g, 2.44 mmol) in DCM (10 mL) was added DMAP(298 mg, 2.44 mmol) and acetyl acetate (622 mg, 6.10 mmol). Afterstirring at 25° C. for 16 h, the reaction mixture was poured intoice-water (50 mL), stirred for 10 min, and extracted with DCM (2×30 mL).The combined organic phase was washed with saturated brine (2×50 mL),dried over anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by flash column (0-20% of EtOAc in PE) to give 21-1 (650 mg,59%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.86 (s, 1H), 7.81 (s, 1H),5.05-4.87 (m, 2H), 2.64-2.57 (m, 1H), 2.34-2.06 (m, 2H), 1.99 (s, 3H),1.87-1.58 (m, 10H), 1.54 (s, 3H), 1.51-1.30 (m, 7H), 1.15-0.82 (m, 4H),0.67 (s, 3H).

Synthesis of 21-2

To a solution of 21-1 (300 mg, 0.66 mmol) in chloroform (5 mL) was addeddropwise DAST (0.79 ml, 5.97 mmol) at 0° C. under N₂. After stirring at60° C. for 12 h, the reaction mixture was quenched with sat. NaHCO₃ (50mL) and extracted with EtOAc (2×30 mL). The combined organic phase waswashed with sat. NaHCO₃ (50 mL), dried over Na₂SO₄, filtered,concentrated. The residue was purified by combi-flash (0-30% of EtOAc inPE) to give 21-2 (65 mg, 20%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.92 (s,1H), 7.82 (s, 1H), 4.59-4.30 (m, 2H), 1.97 (s, 3H), 1.85-1.58 (m, 12H),1.53 (s, 3H), 1.49-1.28 (m, 7H), 1.14-1.03 (m, 5H), 0.88-0.86 (m, 3H)

Synthesis of 21

To a solution of 21-2 (35 mg, 0.074 mmol) in dioxane (0.5 mL) was addedMeOH (1 mL) and NaOH (2.94 ml, 5 M, 14.7 mmol) at 15° C. After stirringat 35° C. for 16 h, the reaction mixture was poured into water (20 mL),stirred for 10 min, and extracted with EtOAc (3×40 mL). The combinedorganic phase was washed with saturated brine (2×50 mL), dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was purified byflash column (0˜40% of EtOAc in PE) and purified by SFC (Method: Column:DAICEL CHIRALPAK AD (250 mm*50 mm, 10 um); Condition: 0.1% NH₃H₂O EtOH;Begin B: 60%; End B: 60%) to afford 21 (14.4 mg, 41%). ¹H NMR (400 MHz,CDCl₃) δ_(H) 7.92 (s, 1H), 7.82 (s, 1H), 4.55-4.34 (m, 2H), 2.02-1.96(m, 1H), 1.86-1.60 (m, 10H), 1.49-1.27 (m, 9H), 1.25 (s, 3H), 1.13-1.05(m, 5H), 0.87 (d, J=3.2 Hz, 3H). LC-ELSD/MS: purity >99%; MS ESI calcd.for C₂₅H₃₅F₂N₃O [M−H₂O+H]⁺ 414.2, found 414.2.

Example 22 & 23: Synthesis of1-((S)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-13-methyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-3-carbonitrile(22) &1-((R)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-13-methyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-3-carbonitrile(23)

To a solution of 7-3 (300 mg, 0.831 mmol) in DMF (5 mL) were added1H-pyrazole-3-carbonitrile (154 mg, 1.66 mmol) and Cs₂CO₃ (1.35 g, 4.15mmol). After stirring at 125° C. for 12 h, the mixture was diluted withwater (100 mL) and extracted with EtOAc (3×50 mL). The combined organiclayer was concentrated and purified by flash column (0-25% of EtOAc inPE) to give mixture of epimers (200 mg, 53%). The epimers were separatedby SFC (Column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um; Condition:0.1% NH₃H₂O IPA; Begin: B 55%; End B: 55%; FlowRate (ml/min): 80) togive 22 (80.5 mg) and 23 (47.2 mg). The regiochemistry of pyrazole wasassigned by HMBC (H22 correlated with C5 in pyrazole ring).

22: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.58 (d, J=4 Hz, 1H), 6.68 (d, J=4 Hz,1H), 4.38-4.35 (m, 1H), 4.13-4.09 (m, 1H), 2.35 (s, 1H), 2.02-1.99 (m,1H), 1.81-1.60 (m, 10H), 1.55-1.31 (m, 7H), 1.28-1.03 (m, 11H),0.96-0.91 (m, 9H). LC-ELSD/MS: purity 99%, MS ESI calcd. forC₂₈H₄₀N₃[M−2H₂O+H]⁺ 418.3, found 418.3. SFC 100% de.

23: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.53 (d, J=4 Hz, 1H), 6.67 (d, J=4 Hz,1H), 4.19-4.16 (m, 1H), 4.05-4.02 (m, 1H), 2.21 (s, 1H), 2.07-2.04 (m,1H), 1.94-1.58 (m, 10H), 1.55-1.25 (m, 11H), 1.22-1.02 (m, 10H),0.95-0.87 (m, 6H). LC-ELSD/MS: purity 99%, MS ESI calcd. forC₂₈H₄₀N₃[M−2H₂O+H]⁺ 418.3, found 418.3. SFC 100% de.

Example 24 & 25: Synthesis of1-((S)-2-((3R,5R,8R,9S,10S,13S,14S,17S)-3-(ethoxymethyl)-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile(24) &1-((R)-2-((3R,5R,8R,9S,10S,13S,14S,17S)-3-(ethoxymethyl)-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile(25)

Synthesis of 24-1

To a mixture of MePPh₃Br (5.67 g, 15.9 mmol) in THE (70 mL) was addedt-BuOK (1.78 mg, 15.9 mmol) at 25° C. under N₂. After stirring at 55° C.for 30 min, 24-0 (2.0 g, 5.31 mmol) in THE (30 mL) was added in portionsblow 55° C. After stirring at 55° C. for 2 h, the reaction mixture waspoured into water (300 mL) at 25° C. and extracted with EtOAc (2×300mL). The combined organic layer was washed with water (300 mL), brine(200 mL), dried over Na₂SO₄, filtered and concentrated in vacuum. Theresidue was purified by silica gel chromatography (0-5% EtOAc in PE) togive 24-1 (900 mg). ¹H NMR (400 MHz, CDCl₃) δ_(H) 4.84 (s, 1H), 4.69 (s,1H), 3.55-3.51 (q, J=6.9 Hz, 2H), 3.47-3.33 (m, 2H), 2.73-2.65 (m, 1H),2.06-1.97 (m, 2H), 1.96-1.81 (m, 3H), 1.77-1.72 (m, 4H), 1.58-1.54 (m,2H), 1.45-1.38 (m, 4H), 1.25-1.18 (m, 8H), 0.90-0.82 (m, 9H), 0.54 (s,3H).

Synthesis of 24-2

To a solution of 24-1 (900 mg, 2.40 mmol) in DCM (20 mL) was addedm-CPBA (974 mg, 85%, 4.80 mmol) at 15° C. After stirring at 15° C. for 1h, the mixture was quenched with saturated NaHCO₃ aqueous (200 mL). Theorganic phase was separated and washed with saturated NaHCO₃/Na₂S₂O₃aqueous (1:1, 3×100 mL), brine (100 mL), dried over Na₂SO₄, filtered andconcentrated under vacuum to give 24-2 (1.0 g). ¹H NMR (400 MHz, CDCl₃)δ_(H) 3.55-3.51 (q, J=6.9 Hz, 2H), 3.47-3.35 (m, 2H), 1.98-1.77 (m, 4H),1.76-1.66 (m, 2H), 1.64-1.44 (m, 6H), 1.43-1.31 (m, 7H), 1.27-1.17 (m,7H), 1.16-0.99 (m, 4H), 0.95-0.90 (m, 3H), 0.81-0.74 (m, 1H), 0.71-0.61(m, 2H).

Synthesis of 24 & 25

To a solution of 24-2 (1.0 g, 2.56 mmol) in DMF (15 mL) were added1H-pyrazole-4-carbonitrile (595 mg, 6.40 mmol) and Cs₂CO₃ (4.17 g, 12.8mmol). After stirring at 125° C. for 12 h, the reaction mixture wasdiluted with water (100 mL) and extracted with EtOAc (3×60 mL). Thecombined organic layer was washed with saturated LiCl (3×150 mL) andthen concentrated. The residue was purified by flash column (0˜20% ofEtOAc in PE) to give a mixture of epimers (700 mg). The epimers wereseparated by SFC (Column: Chiralpak AD-3 50×4.6 mm I.D., 3 um Mobilephase: A: CO₂ B:ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 2min and hold 40% for 1.2 min, then 5% of B for 0.8 min Flow rate: 4mL/min Column temp.: 35° C. ABPR: 1500 psi) afford 24 (284.9 mg, 40.8%)and 25 (88.4 mg, 12.7%).

24: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.92 (s, 1H), 7.82 (s, 1H), 4.36-4.32(d, J=13.8 Hz, 1H), 4.09-4.05 (d, J=13.8 Hz, 1H), 3.53-3.50 (q, J=6.9Hz, 2H), 3.47-3.36 (m, 2H), 2.72 (s, 1H), 2.54 (s, 1H), 2.01-1.99 (d,J=10.8 Hz, 1H), 1.96-1.79 (m, 2H), 1.77-1.64 (m, 4H), 1.62-1.46 (m, 5H),1.45-1.35 (m, 6H), 1.26-1.18 (m, 6H), 1.13-1.08 (m, 1H), 0.96-0.93 (d,J=10.8 Hz, 7H), 0.89 (s, 3H). LC-ELSD/MS purity 99%, MS ESI calcd. forC₂₇H₃₆N₃ [M-EtOH−2H₂O+H] 402.3 found 402.3. SFC 100% de.

25: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.81 (s, 1H), 7.81 (s, 1H), 4.17-4.14(d, J=13.8 Hz, 1H), 4.02-3.99 (d, J=13.8 Hz, 1H), 3.55-3.50 (q, J=7.0Hz, 2H), 3.46-3.35 (m, 2H), 2.72 (s, 1H), 2.34 (s, 1H), 2.06 (d, 1H),1.97-1.79 (m, 3H), 1.73-1.64 (m, 3H), 1.62-1.53 (m, 3H), 1.53-1.34 (m,8H), 1.27-1.18 (m, 6H), 1.17-1.10 (m, 2H), 1.07 (s, 3H), 0.93 (s, 3H),0.85 (s, 3H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₇H₃₆N₃[M-EtOH−2H₂O+H]⁺402.3 found 402.3. SFC 100% de.

Example 26 & 27: Synthesis of1-((S)-2-hydroxy-2-((3R,5R,8R,9S,10S,13S,14S,17S)-3-hydroxy-10,13-dimethyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile(26) &1-((R)-2-hydroxy-2-((3R,5R,8R,9S,10S,13S,14S,17S)-3-hydroxy-10,13-dimethyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile(27)

Synthesis of 26-1

To a mixture of MePPh₃Br (2.96 g, 8.30 mmol) in THE (30 mL) was addedt-BuOK (931 mg, 236 mmol) at 25° C. under N₂. After stirring at 50° C.for 30 min, 26-0 (1.0 g, 2.77 mmol) in THE (20 mL) was added in portionsblow 50° C. After stirring at 50° C. for 2 h, the reaction mixture waspoured into water (300 mL) at 25° C. and extracted with EtOAc (2×300mL). The combined organic layer was washed with water (300 mL), brine(200 mL), dried over Na₂SO₄, filtered and concentrated in vacuum. Theresidue was purified by silica gel chromatography (0-5% EtOAc in PE) togive 26-1 (880 mg, 88.6%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 4.84 (s, 1H),4.69 (s, 1H), 2.06-1.98 (m, 1H), 1.93-1.79 (m, 3H), 1.75 (s, 3H),1.73-1.64 (m, 3H), 1.60-1.49 (m, 3H), 1.48-1.33 (m, 8H), 1.32-1.17 (m,6H), 1.17-0.99 (m, 4H), 0.97-0.90 (m, 6H), 0.54 (s, 3H).

Synthesis of 26-2

To a solution of 26-1 (880 mg, 2.45 mmol) in DCM (20 mL) was addedm-CPBA (994 mg, 85%, 4.90 mmol) at 15° C. After stirring at 15° C. for 1h, the mixture was quenched by saturated NaHCO₃ aqueous (200 mL). Theorganic phase was separated and washed with saturated NaHCO₃/Na₂S₂O₃aqueous (1:1, 3×100 mL), brine (100 mL), dried over Na₂SO₄, filtered andconcentrated under vacuum to give 26-2 (900 mg). ¹H NMR (400 MHz, CDCl₃)δ_(H) 2.89-2.86 (d, J=4.3 Hz, 1H), 2.57-2.53 (d, J=4.3 Hz, 1H),2.51-2.29 (m, 1H), 1.95-1.80 (m, 5H), 1.73-1.64 (m, 2H), 1.63-1.54 (m,4H), 1.39-1.32 (m, 9H), 1.27-1.20 (m, 5H), 0.97-0.88 (m, 10H), 0.77 (s,1H), 0.65 (s, 3H).

Synthesis of 26 & 27

To a solution of 26-2 (900 mg, 2.40 mmol) in DMF (5 mL) were added1H-pyrazole-4-carbonitrile (557 mg, 5.99 mmol) and Cs₂CO₃ (3.87 g, 11.9mmol). After stirring at 125° C. for 12 h, the reaction mixture wasdiluted with water (100 mL) and extracted with EtOAc (3×60 mL). Thecombined organic layer was washed with saturated LiCl (3×150 mL) andthen concentrated. The residue was purified by flash column (0-20% ofEtOAc in PE) to give a mixture of epimers (740 mg, 66.0%). The epimerswere separated by SFC (Column: Chiralpak AD-3 50×4.6 mm I.D., 3 umMobile phase: A: CO₂ B: ethanol (0.05% DEA) Gradient: from 5% to 40% ofB in 2 min and hold 40% for 1.2 min, then 5% of B for 0.8 min Flow rate:4 mL/min Column temp.: 35° C. ABPR: 1500 psi) afford 26 (318.7 mg) and27 (154.0 mg).

26: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.92 (s, 1H), 7.82 (s, 1H), 4.35-4.32(d, J=13.6 Hz, 1H), 4.09-4.05 (d, J=13.8 Hz, 1H), 2.52 (s, 1H),2.05-1.98 (m, 1H), 1.91-1.82 (m, 2H), 1.78-1.63 (m, 4H), 1.57-1.49 (m,5H), 1.48-1.32 (m, 10H), 1.30-1.19 (m, 5H), 1.16-1.02 (m, 4H), 0.97 (s,3H), 0.95-0.92 (m, 5H), 0.89 (s, 3H). LC-ELSD/MS purity 99%, MS ESIcalcd. for C₂₉H₄₁N₃ [M−2H₂O+H]⁺432.3 found 432.3. SFC 100% de.

27: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.89 (s, 1H), 7.80 (s, 1H), 4.21-4.11(m, 1H), 4.02-3.98 (d, J=13.8 Hz, 1H), 2.30 (s, 1H), 2.06 (s, 1H),1.97-1.78 (m, 3H), 1.73-1.63 (m, 3H), 1.55 (s, 3H), 1.52-1.33 (m, 12H),1.32-1.18 (m, 6H), 1.08 (s, 3H), 0.97-0.91 (m, 6H), 0.85 (s, 3H).LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₉H₄₁N₃ [M−2H₂O+H]⁺432.3 found432.3.

Example 28: Synthesis of1-((3-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)oxetan-3-yl)methyl)-1H-pyrazole-4-carbonitrile

Synthesis of 28-1

To a suspension of NaH (2.75 g, 60%, 68.8 mmol) in THE (60 mL) was added(EtO)₂P(O)CH₂COOEt (15.4 g, 68.8 mmol) dropwise at 0° C. After stirringat 20° C. for 10 min, a solution of 28-0 (10 g, 34.4 mmol, reported inpatent ‘WO2014/169833, 2014, A1’) in THF (20 mL) was added dropwise at20° C. After stirring at 70° C. for 16 h, the reaction mixture waspoured into NH₄Cl (200 mL, 10% aq) and extracted with EtOAc (200 mL).The organic layer was separated, dried over Na₂SO₄, filtered,concentrated. The residue was purified by flash column (0˜20% EtOAc inPE) to give 28-1 (12 g, 97%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 5.52 (t,J=2.4 Hz, 1H), 4.15 (q, J=7.2 Hz, 2H), 2.90-2.75 (m, 2H), 1.95-1.60 (m,5H), 1.50-1.25 (m, 18H), 1.20-1.05 (m, 4H), 0.82 (s, 3H).

Synthesis of 28-2

To a solution of 28-1 (12 g, 33.2 mmol) in THF (150 mL) was added Pd/C(2 g, dry, 10%) under N₂. After stirring under H₂ (40 psi) at 40° C. for24 h, the reaction mixture was filtered through a pad of celite whichwas then washed with THE (3×50 mL). The combined filtrate wasconcentrated to give 28-2 (11.7 g, 97.5%). ¹H NMR (400 MHz, CDCl₃) δ_(H)4.11 (q, J=6.8 Hz, 2H), 2.35 (dd, J=5.2, 14.4 Hz, 1H), 2.10 (dd, J=10.0,14.8 Hz, 1H), 2.00-1.75 (m, 6H), 1.70-1.50 (m, 3H), 1.50-1.35 (m, 6H),1.35-1.25 (m, 10H), 1.20-0.95 (m, 6H), 0.59 (s, 3H).

Synthesis of 28-3

To a solution of i-Pr₂NH (1.66 g, 16.5 mmol) in THE (30 mL) was addedBuLi (6.6 mL, 2.5 M in hexane, 16.5 mmol) at −70° C. After warming to 0°C. over 15 min and then cooling to −70° C. a solution of 28-2 (2 g, 5.5mmol) in THF (10 mL) was added. After stirring at −70° C. for 1 h, asolution of ClCOOEt (1.79 g, 16.5 mmol) in THE was added. After stirringat −70° C. for 1 h, the reaction mixture was quenched with NH₄Cl (20 mL,10%) and extracted with EtOAc (2×20 mL). The combined organic layer wasdried over Na₂SO₄, filtered and concentrated in vacuum to give 28-3 (2.7g). ¹H NMR (400 MHz, CDCl₃) δ_(H) 4.25-4.05 (m, 4H), 3.29 (d, J=11.2 Hz,1H), 2.25-2.15 (m, 1H), 2.00-1.75 (m, 4H), 1.70-1.35 (m, 12H), 1.35-1.20(m, 10H), 1.20-0.95 (m, 7H), 0.70 (s, 3H).

Synthesis of 28-4

To a suspension of t-BuOK (4.85 g, 31.0 mmol) in THE (20 mL) was added asolution of 28-3 (2.25 g, 5.17 mmol) in THE (20 mL) at 0° C. Afterstirring at 15° C. for 1 h, BOMCI (3.47 g, 31.0 mmol) was added at 0° C.After stirring at 0° C. for 1 h, the reaction mixture was poured intoNH₄Cl (100 mL, sat.) and extracted with EtOAc (100 mL). The organiclayer was separated, dried over Na₂SO₄, filtered and concentrated togive 28-4 (8.5 g) which contain some diethyl2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-((benzyloxy)methoxy)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-((benzyloxy)methyl)malonate.

Synthesis of 28-5

To a suspension of LiAlH₄ (1.96 g, 51.7 mmol) in THE (80 mL) was added asolution of 28-4 (5.17 mmol mixture) in THE (20 mL) dropwise at 0° C.After stirring at 0° C. for 1 h, the reaction mixture was quenched withwater/THF (2 mL/100 mL) followed by NaOH (2 mL, 10%) and water (6 mL).The mixture was filtered and the residue was washed with THF (3×50 mL).The combined filtrate was concentrated to 100 mL and HCl (2 M, 10 mL)was added. After stirring at 50° C. for 1 h, the reaction mixture wasdiluted with NaHCO₃ (50 mL, sat) and extracted with EtOAc (100 mL). Theorganic layer was separated, dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by flash column (30˜80% EtOAc inPE) to give 28-5 (1 g, 41% above two steps). ¹H NMR (400 MHz, CDCl₃)δ_(H) 7.45-7.30 (m, 5H), 4.50 (s, 2H), 3.95-3.55 (m, 6H), 2.80-2.70 (br,1H), 2.70-2.60 (br, 1H), 1.95-1.70 (m, 4H), 1.70-1.50 (m, 5H), 1.50-1.20(m, 13H), 1.15-0.90 (m, 6H), 0.73 (s, 3H).

Synthesis of 28-6

To a solution of 28-5 (1 g, 2.12 mmol) in THF (20 mL) was added BuLi(1.01 mL, 2.5 M in hexane, 2.54 mmol) at 0° C. After stirring at 0° C.for 10 min, a solution of TsCl (484 mg, 2.54 mmol) in THE (5 mL) wasadded. After stirring at 0° C. for 1 h, BuLi (1.01 mL, 2.5 M in hexane,2.54 mmol) was added at 0° C. After stirring at 15° C. for 2 h, thereaction mixture was quenched with NH₄Cl (20 mL, sat.) and extractedwith EtOAc (2×30 mL). The combined organic layer was dried over Na₂SO₄,filtered, and concentrated under vacuum. The residue was purified byflash column (0˜15% EtOAc in PE) to give 28-6 (650 mg, 68%). ¹H NMR (400MHz, CDCl₃) δ_(H) 7.45-7.30 (m, 5H), 4.83 (d, J=6.4 Hz, 1H), 4.60 (d,J=12.0 Hz, 1H), 4.55-4.50 (m, 2H), 4.44 (d, J=5.6 Hz, 1H), 4.23 (d,J=6.4 Hz, 1H), 3.89 (d, J=9.2 Hz, 1H), 3.66 (d, J=9.2 Hz, 1H), 2.20-2.10(m, 1H), 2.00-1.60 (m, 8H), 1.50-1.30 (m, 7H), 1.30-0.95 (m, 12H), 0.52(s, 3H).

Synthesis of 28-7

To a solution of 28-6 (650 mg, 1.43 mmol) in THE (20 mL) was added Pd/C(0.5 g, 10%, wet) under N₂. After stirring under H₂ (20 psi) at 20° C.for 20 h, the reaction mixture was filtered and the residue was washedwith THF (20 mL). The combined filtrate was concentrated and purified byflash column (40˜70% EtOAc in PE) to give 28-7 (380 mg, 73%). ¹H NMR(400 MHz, CDCl₃) δ_(H) 4.85 (d, J=6.8 Hz, 1H), 4.54 (d, J=5.6 Hz, 1H),4.46 (d, J=5.6 Hz, 1H), 4.24 (d, J=6.4 Hz, 1H), 4.08 (dd, J=4.0, 10.8Hz, 1H), 3.82 (d, J=10.0 Hz, 1H), 2.20-2.10 (m, 1H), 2.00-1.65 (m, 10H),1.55-1.00 (m, 18H), 0.53 (s, 3H). LC-ELSD/MS: purity>99%, MS ESI calcd.for C₂₃H₃₇O₂[M+H-H₂O]⁺ 345.3, found 345.3.

Synthesis of 28-8

To a solution of 28-7 (185 mg, 0.51 mmol) in DCM (5 mL) were addedN-Me-Im (41.8 mg, 0.51 mmol), TEA (258 mg, 2.55 mmol) and TsCl (194 mg,1.02 mmol). After stirring at 15° C. for 16 h, the reaction mixture waswashed with water (5 mL), dried over Na₂SO₄, filtered, and concentrated.The residue was purified by flash column (0-25% EtOAc in PE/DCM (1:1))to give 28-8 (200 mg, 76%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.83 (d, J=8.4Hz, 2H), 7.37 (d, J=8.0 Hz, 2H), 4.82 (d, J=6.8 Hz, 1H), 4.50-4.40 (m,2H), 4.22 (d, J=9.6 Hz, 1H), 4.18 (d, J=6.0 Hz, 1H), 4.11 (d, J=6.8 Hz,1H), 2.46 (s, 3H), 2.10-2.00 (m, 1H), 1.95-1.55 (m, 8H), 1.50-0.90 (m,19H), 0.47 (s, 3H).

Synthesis of 28

To a solution of 28-8 (200 mg, 0.39 mmol) in DMF (5 mL) were added4-cyano-pyrazole (72 mg, 0.77 mmol), KI (64.2 mg, 0.38 mmol) and K₂CO₃(108 mg, 0.77 mmol). After stirring at 80° C. for 16 h, the reactionmixture was poured into water (30 mL) and filtered. The residue waspurified by flash column (20˜50% EtOAc in PE), dissolved in MeCN (30mL)/water (30 mL) and lyophilized to give 28 (135.7 mg, 79%). ¹H NMR(400 MHz, CDCl₃) δ_(H) 7.88 (s, 1H), 7.83 (s, 1H), 4.96 (d, J=6.8 Hz,1H), 4.70-4.60 (m, 2H), 4.53 (d, J=6.4 Hz, 1H), 4.47 (d, J=7.2 Hz, 1H),4.35 (d, J=14.0 Hz, 1H), 2.10-2.00 (m, 1H), 2.00-1.65 (m, 8H), 1.55-0.95(m, 19H), 0.69 (s, 3H). LC-ELSD/MS purity>99%, MS ESI calcd. forC₂₇H₄₀N₃O₂ [M+H]⁺ 438.3, found 438.3.

EXAMPLE 29 & 30: Synthesis of1-((S)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile(29 &1-((R)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile(30)

Synthesis of 29.2

To a solution of MePPh₃Br (12.2 g, 34.0 mmol) in THE (20 mL) was addedt-BuOK (2.88 g, 25.8 mmol) at 15° C. After stirring for 1 h at 15° C.,29.1 (3 g, 8.60 mmol) in THE (20 mL) was added. After stirring at 45° C.for 3 h, the mixture was treated with saturated NH₄Cl (50 mL) andextracted with EtOAc (2×30 mL). The combined organic solution was washedwith brine (100 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash column (0˜40% of EtOAcin PE) to give 29.2 (4.5 g). ¹H NMR (400 MHz, CDCl₃) δ 4.83 (s, 1H),4.45 (s, 1H), 3.47-3.31 (m, 5H), 2.61 (s, 1H), 2.05-2.02 (m, 1H),1.91-1.77 (m, 4H), 1.74 (s, 3H), 1.68-1.52 (m, 5H), 1.49-1.31 (m, 7H),1.28-1.04 (m, 7H), 0.59-0.50 (m, 3H).

Synthesis of 29.3

To a solution of 29.2 (500 mg, 1.44 mmol) in DCM (20 mL) was addedm-CPBA (461 mg, 2.15 mmol, 85%) at 15° C. After stirring for 1 h, themixture was quenched with sat.NaHCO₃ and Na₂S₂O₃ (40 mL, v:v=1:1) andextracted with DCM (2×20 mL). The combined organic phase was washed withsat.NaHCO₃ and Na₂S₂O₃ (50 mL, v:v=1:1), dried over Na₂SO₄, filtered andconcentrated to give 29.3 (520 mg). ¹H NMR (400 MHz, CDCl₃)δ_(H)=3.46-3.32 (m, 8H), 2.88 (d, J=4.4 Hz, 1H), 2.55 (d, J=4.4 Hz, 1H),2.51-2.47 (m, 1H), 2.31 (d, J=5.2 Hz, 1H), 2.04-1.98 (m, 1H), 1.95-1.53(m, 8H), 1.50-1.29 (m, 8H), 1.28-0.98 (m, 5H), 0.82-0.78 (m, 1H), 0.68(s, 3H).

Synthesis of 29.4

To solution of 29.3 (520 mg, 1.43 mmol) in DMF (10 mL) wer added Cs₂CO₃(1.39 g, 4.29 mmol) and 1H-pyrazole-4-carbonitrile (332 mg, 3.57 mmol)at 15° C. under N₂. After stirring at 130° C. for 12 h, the mixture wasadded into saturated NH₄Cl (50 mL) and extracted with EtOAc (3×50 mL).The combined organic layer was washed with LiCl (100 mL, 5% in water),brine (2×100 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by column (0˜50% of EtOAc in PE)to afford 29.4 (650 mg). LC-ELSD/MS purity 99%, MS ESI calcd forC₂₆H₃₅N₃[M−2H₂O—CH₃OH+H]⁺ 388.3, found 388.3.

Separation of 29 & 30

29.4 was separated by SFC (Column: Chiralcel OD-3 50_(i)Á4.6 mm I.D., 3um; Mobile phase: A: CO₂ B:ethanol (0.05% DEA); Gradient: from 5% to 40%of B in 2 min and hold 40% for 1.2 min, then 5% of B for 0.8 min; Flowrate: 4 mL/min) to afford 30 (73 mg, 18.2%) and 29 (189.9 mg, 47.3%).

29: ¹H NMR (400 MHz, CDCl₃) δ_(H)=7.92 (s, 1H), 7.82 (s, 1H), 4.36 (d,J=13.6 Hz, 1H), 4.08 (d, J=13.6 Hz, 1H), 3.46-3.33 (m, 5H), 2.59 (s,1H), 2.52 (s, 1H), 2.01 (br d, J=12.0 Hz, 1H), 1.87-1.57 (m, 9H),1.52-1.31 (m, 7H), 1.29-1.04 (m, 7H), 0.96 (s, 3H), 0.91 (s, 3H)LC-ELSD/MS purity 99%, MS ESI calcd for C₂₆H₃₅N₃[M−2H₂O—CH₃OH+H]⁺ 388.3,found 388.3.

30: ¹H NMR (400 MHz, CDCl₃) δ_(H)=7.89 (s, 1H), 7.80 (s, 1H), 4.17 (d,J=13.6 Hz, 1H), 4.01 (d, J=13.6 Hz, 1H), 3.48-3.32 (m, 5H), 2.60 (s,1H), 2.32 (s, 1H), 2.06 (br d, J=13.6 Hz, 1H), 1.98-1.60 (m, 9H),1.51-1.24 (m, 9H), 1.08 (s, 8H), 0.87 (s, 3H). LC-ELSD/MS purity 99%, MSESI calcd for C₂₆H₃₅N₃[M−2H₂O—CH₃OH+H]⁺ 388.3, found 388.3.

EXAMPLE 31: Synthesis of1-(1-((S)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazol-4-yl)ethanone(31)

Synthesis of 31.1

To a solution of 21.0 (2 g, 4.88 mmol), 2,6-dimethylpyridine (1.30 g,12.2 mmol) in DCM (20 mL) was added dropwise tert-butyldimethylsilyltrifluoromethanesulfonate (2.57 g, 9.76 mmol) at 0° C. After stirring at15° C. for 5 hrs, the reaction mixture was quenched with water (60 mL)and extracted with DCM (2×50 mL). The combined organic phase washed withbrine (50 mL), dried over Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by flash column (10-20% of EtOAc in PE)to afford 31.1 (2.5 g, 98.0%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.87 (s,1H), 7.82 (s, 1H), 5.10-4.97 (m, 1H), 4.96-4.84 (m, 1H), 2.72-2.60 (m,1H), 2.28-2.17 (m, 1H), 2.09-2.02 (m, 1H), 1.87-1.67 (m, 7H), 1.46-1.40(m, 4H), 1.29-1.26 (m, 3H), 1.24 (s, 4H), 1.16-1.07 (m, 3H), 0.88 (s,11H), 0.68 (s, 3H), 0.09 (s, 6H).

Synthesis of 31.2

To a solution of 31.1 (200 mg, 0.381 mmol) in THE (5 mL) was addedMeMgBr (1.27 mL, 3.81 mmol, 3.0 M) at −60° C. After stirring at 25° C.for 2 h, the mixture was added to NH₄Cl (20 mL). and extracted withEtOAc (2×15 mL). The combined organic layers were washed with brine (15mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residuewas purified by flash column (0˜20% of EtOAc in PE) to give 31.2 (120mg, 56.6%). ¹H NMR (400 MHz, CDCl3) δ_(H) 7.94-7.93 (m, 1H), 7.92-7.90(m, 1H), 4.41-4.30 (m, 1H), 4.08-4.00 (m, 1H), 2.68-2.62 (m, 1H),2.45-2.44 (m, 3H), 2.28-2.17 (m, 1H), 2.11-2.02 (m, 2H), 1.81-1.74 (m,8H), 1.44 (s, 3H), 1.24 (s, 6H), 1.15-1.06 (m, 6H), 1.01-0.93 (m, 4H),0.88 (s, 9H), 0.70-0.68 (m, 3H), 0.09 (s, 6H), 0.10-0.09 (m, 1H).

Synthesis of 31

To a solution of 31.2 (120 mg, 0.215 mmol) in THE (2 mL) was added HF(21.4 mg, 1.07 mmol, 1.1 g/mL) in one portion at 25° C. under N₂. Afterstirring at 25° C. for 16 h, the mixture was added to NH₄Cl (10 mL) andextracted with EtOAc (2×15 mL). The combined organic layers were washedwith brine (15 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by HPLC (Welch Xtimate C18 150×25mm, 5 um; Condition: water (0.04% NH₃H₂O)-ACN; Gradient: from 50% to 80%of B in 8.5 min and hold 100% for 2 min; Flow rate: 30 mL/min;Injections: 6) to afford 31 (3.8 mg, 3.99%). ¹H NMR (400 MHz, CDCl3)δ_(H) 7.97-7.95 (m, 1H), 7.95-7.93 (m, 1H), 4.38-4.31 (m, 1H), 4.06-4.01(m, 1H), 3.08-3.05 (m, 1H), 2.46 (s, 3H), 2.08-2.02 (m, 1H), 1.87-1.73(m, 5H), 1.70-1.61 (m, 4H), 1.47-1.35 (m, 8H), 1.27 (s, 5H), 1.14-1.04(m, 5H), 1.00 (s, 3H), 0.93 (s, 3H). LC-ELSD/MS purity 99%, MS ESIcalcd. for C₂₇H₄₂N₂O₃ [M+H]⁺ 443.3 found 443.3.

EXAMPLES 32 & 33: Synthesis of1-((R)-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methoxypropyl)-1H-pyrazole-4-carbonitrile(32) &1-[(2S)-2-[(1S,3aS,3bR,5aR,7R,9aS,9bR,11aS)-7-hydroxy-7-(methoxymethyl)-11a-methyl-hexadecahydro-1H-cyclopenta[a]phenanthren-1-yl]-2-methoxypropyl]-1H-pyrazole-4-carbonitrile(33)

Synthesis of 32.1

To a solution of 29.2 (4 g, 11.5 mmol) and 2,6-dimethylpyridine (6.14 g,57.4 mmol) in DCM (150 mL) was added TBSOTf (12.1 g, 46.0 mmol) at 0° C.After stirring at 25° C. for 16 h, the mixture was diluted with DCM (150mL) and washed with water (300 mL). The organic phase was separated,dried over anhydrous Na₂SO₄, filtered and concentrated to give 32.1 (6g), which was used directly for the next step. ¹H NMR (400 MHz, CDCl₃) δ4.85 (s, 1H), 4.70 (s, 1H), 3.42-3.29 (m, 5H), 2.11-2.05 (m, 1H),1.89-1.79 (m, 5H), 1.72-1.56 (m, 8H), 1.49-0.99 (m, 16H), 0.95-0.88 (m,6H), 0.57 (s, 3H), 0.08-0.05 (m, 6H).

Synthesis of 32.2

To a solution of 32.1 (3 g, 6.51 mmol) in DCM (150 mL) was added m-CPBA(1.96 g, 9.76 mmol, 85%). After stirring at 25° C. for 2 h, the reactionmixture was quenched with NaHCO₃ (150 mL, sat.) and extracted with DCM(2×80 mL). The combined organic phase was washed with brine (150 mL),dried over anhydrous Na₂SO₄, filtered and concentrated to give 32.2 (2.3g).

Synthesis of 32.3 & 32.4

To a solution of 32.2 (2.3 g, 4.82 mmol) in DMF (50 mL) were added1H-pyrazole-4-carbonitrile (1.34 g, 14.4 mmol) and Cs₂CO₃ (4.69 g, 14.4mmol) at 25° C. After stirring at 140° C. for 8 h, the mixture wasdiluted with water (100 mL) and extracted with EtOAc (2×60 mL). Thecombined organic phase was washed with water (100 mL), brine (100 mL),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum. Theresidue was purified by flash column (0%-30% of EtOAc in PE) to give32.4 (1.3 g, 47.4%) and 32.3 (680 mg, 24.8%).

32.3: ¹H NMR (400 MHz, CDCl₃) δ 7.89 (s, 1H), 7.80 (s, 1H), 4.23-4.13(m, 1H), 4.05-3.90 (m, 1H), 3.43-3.26 (m, 5H), 2.29 (s, 1H), 2.10-2.05(m, 1H), 1.98-1.62 (m, 8H), 1.57-1.27 (m, 7H), 1.23-0.97 (m, 10H),0.94-0.81 (m, 13H), 0.06 (s, 6H).

32.4: ¹H NMR (400 MHz, CDCl₃) δ 7.93 (s, 1H), 7.82 (s, 1H), 4.36 (d,J=14.0 Hz, 1H), 4.10-4.05 (m, 1H), 3.41-3.29 (m, 5H), 2.50 (s, 1H),1.83-1.59 (m, 9H), 1.53-1.27 (m, 7H), 1.24-1.01 (m, 8H), 1.00-0.90 (m,6H), 0.85 (s, 9H), 0.06 (s, 6H).

Synthesis of 32.5

To a solution of 32.3 (680 mg, 1.19 mmol) in THE (20 mL) was added NaH(71.1 mg, 1.78 mmol, 60% in oil) at 25° C. under N₂. After stirring at25° C. for 30 min, MeI (337 mg, 2.38 mmol) was added. After stirring at25° C. for 16 h, the reaction mixture was poured into water (50 mL) andextracted with EtOAc (2×50 mL). The combined organic phase was washedwith brine (2×50 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash column (0-20% of EtOAcin PE) to give 32.5 (600 mg).

Synthesis of 32

To a solution of 32.5 (1.3 g, 2.22 mmol) in THE (20 mL) was added TBAF(22.2 mL, 22.2 mmol, 1M in THF). After stirring at 80° C. for 16 h, thereaction mixture was quenched with NH₄Cl (50 mL, sat.) and extractedwith EtOAc (2×50 mL). The combined organic phase was washed with brine(2×50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. Theresidue was purified by flash column (0-50% of EtOAc in PE) to give 32(301.8 mg, 28.9%). ¹H NMR (400 MHz, CDCl₃) δ 7.91 (s, 1H), 7.75 (s, 1H),4.33-4.12 (m, 2H), 3.45-3.32 (m, 5H), 3.18 (s, 3H), 2.57 (s, 1H),1.98-1.91 (m, 1H), 1.85-1.59 (m, 9H), 1.50-1.22 (m, 8H), 1.18-1.00 (m,9H), 0.85 (s, 3H). LCMS 30-90AB_2 min_E, purity>99%, MS ESI calcd. forC₂₇H₃₈N₃O [M+H-MeOH−H₂O]⁺420.3, found 420.2.

Synthesis of 32.6

To a solution of 32.4 (1.3 g, 2.28 mmol) in THE (20 mL) was added NaH(136 mg, 3.42 mmol, 60% in oil) at 25° C. under N₂. After stirring for30 min, MeI (647 mg, 4.56 mmol) was added at 25° C. After stirring at25° C. for 16 h, the reaction mixture was poured into water (50 mL) andextracted with EtOAc (2×50 mL). The combined organic phase was washedwith brine (2×50 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash column (0-20% of EtOAcin PE) to give 32.6 (1.2 g).

Synthesis of 33

To a solution of 32.6 (600 mg, 1.02 mmol) in THE (10 mL) was added TBAF(5.10 mL, 5.10 mmol, 1M in THF). After stirring at 80° C. for 16 h, thereaction mixture was quenched with NH₄Cl (50 mL, sat.) and extractedwith EtOAc (2×50 mL). The combined organic phase was washed with brine(2×50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. Theresidue was purified by flash column (0-50% of EtOAc in PE) to give 33(144.7 mg, 30%). ¹H NMR (400 MHz, CDCl₃) δ 7.90 (s, 1H), 7.75 (s, 1H),4.24 (s, 2H), 3.45-3.34 (m, 5H), 3.13 (s, 3H), 2.59 (s, 1H), 2.09-1.99(m, 1H), 1.86-1.59 (m, 9H), 1.49-1.19 (m, 9H), 1.13-0.98 (m, 8H), 0.81(s, 3H). LCMS purity>99%, MS ESI calcd. for C₂₇H₃₈N₃O[M+H-MeOH−H₂O]+420.3, found 420.2.

EXAMPLES 34 & 35: Synthesis of1-((S)-2-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-2-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile(34) &1-((R)-2-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-2-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile(35)

Synthesis of 34.1

To a solution of 34.0 (100 g, 364 mmol) in DCM (1000 mL) were addedimidazole (49.5 g, 728 mmol) and TBSCl (109 g, 728 mmol) at 25° C. Afterstirring at 25° C. for 2 h, the mixture was poured into water (500 mL)and extracted with DCM (2×500 mL). The combined organic phase was washedwith brine (500 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was triturated from PE (200 mL) at 25° C. togive 34.1 (83 g). ¹H NMR (400 MHz, CDCl₃) δ_(H) 5.82 (s, 1H), 3.56 (t,J=8.3 Hz, 1H), 2.50-2.36 (m, 2H), 2.32-2.19 (m, 3H), 2.14-2.04 (m, 1H),1.94-1.74 (m, 3H), 1.59-1.21 (m, 6H), 1.07-0.90 (m, 4H), 0.88 (s, 9H),0.84-0.78 (m, 1H), 0.76 (s, 3H), 0.00 (d, J=2.8 Hz, 6H).

Synthesis of 34.2

To a solution of 34.1 (50 g, 128 mmol) in THE (300 mL) was added LiHMDS(128 mL, 1 M in THF, 128 mmol) at −70° C. under N₂. After stirring at−70° C. for 30 min, HMPA (22.9 g, 22.4 mL, 128 mmol) was added under N₂.After stirring at −70° C. for 30 min, EtI (199 g, 102 mL, 128 mmol) wasadded under N₂. After stirring at 20° C. for 1 h, the mixture was cooledand concentrated with reduced pressure at 40° C. The residue was pouredinto NH₄Cl (500 mL), stirred for 20 mins, and extracted with EtOAc(3×400 mL). The combined organic phase was washed with brine (2×200 mL),dried over anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by flash column (0˜1% of EtOAc in PE) to give 34.2 (40 g). ¹HNMR (400 MHz, CDCl₃) δ_(H) 5.79 (s, 1H), 5.72 (s, 1H), 3.57 (t, J=8.3Hz, 1H), 2.48-2.39 (m, 1H), 2.34-2.06 (m, 4H), 1.96-1.61 (m, 3H), 1.26(br d, J=1.8 Hz, 9H), 1.07-0.98 (m, 2H), 0.93 (br t, J=7.5 Hz, 4H), 0.88(s, 10H), 0.76 (s, 3H), 0.01 (d, J=2.8 Hz, 6H).

Synthesis of 34.3

To a mixture of 34.2 (20 g, 47.9 mmol) in THE (200 mL) was added Pd/C (2g, 10%). The mixture was degassed under vacuum and purged with H₂ threetimes. After stirring under H₂ (15 psi) at 25° C. for 24 h, the reactionmixture was filtered through a pad of Celite and washed with THE (3×500mL). The filtrate was concentrated to give 34.3 (18 g). ¹H NMR (400 MHz,CDCl₃) δ_(H) 3.61-3.52 (m, 1H), 2.67-2.55 (m, 1H), 2.34-2.05 (m, 4H),1.94-1.62 (m, 4H), 1.58-0.92 (m, 14H), 0.92-0.85 (m, 13H), 0.73 (d,J=3.8 Hz, 3H), 0.00 (dd, J=3.0, 4.4 Hz, 6H).

Synthesis of 34.4

To a solution of BHT (60 g, 272 mmol) in toluene (200 mL) under N₂ at 0°C. was added trimethylaluminum (68 mL, 2 M in toluene, 136 mmol)dropwise slowly. After stirring at 0° C. for 1 h, the MAD solution wasused directly without further purification. To the MAD (64.8 g intoluene, 135 mmol) solution was added a solution of 34.3 (19 g, 45.3mmol) in DCM (200 mL) dropwise at −70° C. under N₂. After stirring at−70° C. for 1 h under N₂, MeMgBr (30.2 mL, 3M in ethyl ether, 90.6 mmol)was added dropwise at −70° C. After stirring for 2 h, the reactionmixture was poured slowly into aqueous citric acid (500 mL, sat.) at 10°C. and extracted with DCM (2×200 mL). The combined organic phase waswashed with brine (300 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash column (0-5% of EtOAc inPE) to give 34.4 (11 g). ¹H NMR (400 MHz, CDCl₃) δ_(H) 3.54 (t, J=8.3Hz, 1H), 2.03-1.94 (m, 1H), 1.91-1.61 (m, 6H), 1.58-1.36 (m, 5H),1.32-1.13 (m, 6H), 1.12-0.89 (m, 11H), 0.87 (s, 11H), 0.70 (d, J=2.3 Hz,3H), 0.00 (t, J=2.6 Hz, 6H).

Synthesis of 34.5 & 34.5a

To a solution of 34.4 (11 g, 25.3 mmol) in THE (20 mL) was addedTBAF.3H₂O (126 ml, 1M, 126 mmol) at 15° C. After stirring at 55° C. for12 h, the mixture was poured into water (200 mL) and extracted withEtOAc (2×200 mL). The organic layer was washed with brine (2×20 mL),dried over anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by column (10-15% of EtOAc in PE) to give 34.5a (3.8 g) and34.5 (4.7 g).

34.5a: ¹H NMR (400 MHz, CDCl₃) δ_(H) 3.63 (br t, J=8.3 Hz, 1H),2.11-1.98 (m, 2H), 1.84-1.73 (m, 3H), 1.61-1.54 (m, 2H), 1.48-1.33 (m,3H), 1.32-1.12 (m, 6H), 1.06 (s, 6H), 1.02-0.82 (m, 8H), 0.74 (s, 4H),0.67-0.58 (m, 1H).

34.5: ¹H NMR (400 MHz, CDCl₃) δ_(H) 3.64 (t, J=8.6 Hz, 1H), 2.12-1.92(m, 3H), 1.85-1.54 (m, 4H), 1.52-1.36 (m, 6H), 1.32-1.16 (m, 5H), 1.09(s, 4H), 1.06 (br s, 4H), 0.95-0.81 (m, 6H), 0.73 (s, 3H).

Synthesis of 34.6

To a mixture of 34.5 (4.7 g, 14.6 mmol) in DCM (50 mL) was added DMP(12.3 g, 29.2 mmol) at 25° C. After stirring at 25° C. for 1 h, themixture was quenched with saturated NaHCO₃ and Na₂S₂O₃ (20 mL, v/v=1/1)and extracted with DCM (2×10 mL). The combined organic phase was washedwith saturated NaHCO₃ and Na₂S₂O₃ (20 mL, v/v=1/1), dried over anhydrousNa₂SO₄, filtered and concentrated to give 34.6 (3 g). ¹H NMR (400 MHz,CDCl₃) δ_(H) 2.43 (dd, J=8.3, 19.3 Hz, 1H), 2.14-1.59 (m, 9H), 1.57-1.40(m, 5H), 1.38-1.12 (m, 8H), 1.10 (s, 3H), 1.08-1.02 (m, 1H), 0.95-0.88(m, 1H), 0.90 (d, J=4.8 Hz, 3H), 0.86 (s, 3H).

Synthesis of 34.7

To a suspension of PPh₃EtBr (10.4 g, 28.2 mmol) in THE (90 mL) was addedt-BuOK (3.16 g, 28.2 mmol). After stirring at 40° C. for 30 min, asolution of 34.6 (3 g, 9.41 mmol) in THF (10 mL) was added into thereaction at 40° C. After stirring at 40° C. for 12 h, the mixture waspoured into NH₄Cl (100 mL, sat.) and extracted with EtOAc (2×100 mL).The combined organic phase was washed with brine (2×100 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue waspurified by flash column (0-5% of EtOAc in PE) to give 34.7 (5 g). ¹HNMR (400 MHz, CDCl₃) δ_(H) 5.10 (tq, J=1.9, 7.2 Hz, 1H), 2.40-2.10 (m,3H), 2.01-1.93 (m, 1H), 1.82 (br d, J=6.5 Hz, 2H), 1.65 (td, J=2.0, 7.1Hz, 9H), 1.55-1.37 (m, 5H), 1.22-1.12 (m, 4H), 1.09 (s, 5H), 0.90 (d,J=5.5 Hz, 4H), 0.87 (s, 4H).

Synthesis of 34.8

To a solution of 34.7 (5 g, 15.1 mmol) in THE (100 mL) was added 9-BBNdimer (7.30 g, 30.2 mmol) under N₂. After stirring at 50° C. under N₂for 2 h, the mixture was cooled to 0° C. and sequentially treated withEtOH (12.8 mL, 226 mmol), NaOH (45.2 mL, 5M, 226 mmol) and H₂O₂(22.6 mL,10 M, 226 mmol) dropwise at 15° C. After stirring at 50° C. for 2 h, themixture was cooled, poured into H₂O (500 mL) and extracted with EtOAc(2×500 mL). The organic layer was checked by potassium iodide-starchtest paper to confirm excess H₂O₂ was destroyed (did not changed toblue). The combined organic phase was washed with aqueous Na₂S₂O₃ (2×800mL, sat.) and brine (800 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash column (0-15% of EtOAcin PE) to give 34.8 (1.8 g). ¹H NMR (400 MHz, CDCl₃) δ_(H) 3.75-3.65 (m,1H), 2.00-1.78 (m, 6H), 1.77-1.68 (m, 2H), 1.60-1.25 (m, 13H), 1.22 (d,J=6.3 Hz, 4H), 1.09 (s, 5H), 0.94-0.80 (m, 6H), 0.66 (s, 3H).

Synthesis of 34.9

To a mixture of 34.8 (1.7 g, 4.87 mmol) in DCM (50 mL) was added DMP(4.13 g, 9.74 mmol) at 25° C. After stirred at 25° C. for 1 h, themixture was quenched with saturated NaHCO₃ and Na₂S₂O₃ (80 mL, v/v=1/1)and extracted with DCM (2×10 mL). The combined organic phase was washedwith saturated NaHCO₃ and Na₂S₂O₃ (20 mL, v/v=1/1), dried over anhydrousNa₂SO₄, filtered and concentrated to give 34.9 (1.8 g). ¹H NMR (400 MHz,CDCl₃) δ_(H) 2.59-2.47 (m, 2H), 2.28-2.15 (m, 1H), 2.11 (s, 3H),2.05-1.92 (m, 3H), 1.85-1.80 (m, 2H), 1.76-1.66 (m, 1H), 1.50.1.38 (m,5H), 1.35-1.16 (m, 6H), 1.10 (s, 3H), 1.08-1.01 (m, 2H), 1.08-1.01 (m,2H), 0.90 (br d, J=4.8 Hz, 5H), 0.60 (s, 3H).

Synthesis of 34.10

To a mixture of MePPh₃Br (5.10 g, 14.3 mmol) in THE (45 mL) was addedt-BuOK (1.60 g, 14.3 mmol) at 25° C. under N₂. After stirring at 25° C.for 30 mins, 34.9 (500 mg, 1.44 mmol) in THE (5 mL) was added at 25° C.After stirring at 60° C. for 3 h, the reaction mixture was cooled,poured into NH₄Cl (50 ml) and extracted with EtOAc (2×50 mL). Thecombined organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash column (0˜10% of EtOAcin PE) to give 34.10 (450 mg). ¹H NMR (400 MHz, CDCl₃) δ_(H) 4.85 (s,1H), 4.70 (s, 1H), 2.08-1.93 (m, 2H), 1.89-1.80 (m, 3H), 1.76 (s, 4H),1.73-1.60 (m, 2H), 1.55 (s, 2H), 1.52-1.36 (m, 4H), 1.29 (br s, 3H),1.10 (s, 4H), 1.08-0.98 (m, 3H), 0.90 (br d, J=5.0 Hz, 6H), 0.57 (s,3H).

Synthesis of 34.11

To a solution of 34.10 (350 mg, 1.01 mmol) in DCM (20 mL) was addedm-CPBA (409 mg, 85%, 2.02 mmol) at 15° C. After stirring at 15° C. for 1h, the mixture was quenched by NaHCO₃ aqueous (50 mL, sat.). The DCMphase was separated and washed with NaHCO₃/Na₂S₂O₃ aqueous (1:1, 3×50mL), brine (50 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum to give 34.11 (400 mg). ¹H NMR (400 MHz,CDCl₃) δ_(H) 2.92-2.53 (m, 2H), 2.50.2.27 (m, 1H), 2.08-1.69 (m, 2H),1.35 (s, 11H), 1.25 (br s, 7H), 1.10 (s, 5H), 0.89 (br d, J=4.8 Hz, 7H),0.82-0.77 (m, 1H), 0.80 (s, 1H), 0.73-0.65 (m, 3H).

Synthesis of 34 & 35

To a solution of 34.11 (400 mg, 1.10 mmol) in DMF (15 mL) were addedCs₂CO₃ (1.07 mg, 3.30 mmol) and 1H-pyrazole-4-carbonitrile (204 mg, 2.20mmol). After stirring at 130° C. for 12 h, the mixture was added intoNH₄Cl (50 Ml, sat.) and extracted with EtOAc (3×50 mL). The combinedorganic layer was washed with LiCl (100 mL, 5% in water), brine (2×100mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residuewas purified by flash column (0˜50% of EtOAc in PE) to give product (450mg), which was purified by SFC (Column: DAICEL CHIRALCEL OD-H (250 mm×30mm, 5 um); Condition: 0.1% NH₃H₂O ETOH; Begin B:30%; End B:30%) toafford 34 (135.6 mg, 19.5%, Rt=3.132 min) and 35 (23.8 mg, 47.6%,Rt=3.383 min).

34: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.92 (s, 1H), 7.82 (s, 1H), 4.35 (d,J=13.8 Hz, 1H), 4.08 (d, J=13.8 Hz, 1H), 2.54 (s, 1H), 2.07-1.89 (m,2H), 1.84-1.79 (m, 2H), 1.78-1.71 (m, 3H), 1.68-1.60 (m, 2H), 1.51-1.38(m, 4H), 1.34-1.15 (m, 7H), 1.09 (s, 4H), 1.08-1.03 (m, 3H), 0.97 (s,3H), 0.92 (s, 3H), 0.89 (br d, J=4.0 Hz, 5H). LC-ELSD/MS purity 99%, MSESI calcd. for C₂₈H₄₀N₃[M−2H₂O+H]⁺418.3 found 418.3. SFC 99% de.

35: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.89 (s, 1H), 7.80 (s, 1H), 4.19-4.12(m, 1H), 4.04-3.97 (m, 1H), 2.29 (s, 1H), 2.08 (br d, J=12.3 Hz, 1H),1.99-1.89 (m, 2H), 1.82 (br d, J=6.8 Hz, 2H), 1.76-1.60 (m, 5H),1.52-1.38 (m, 4H), 1.32-1.18 (m, 6H), 1.10 (d, J=3.3 Hz, 10H), 0.93-0.84(m, 8H). LC-ELSD/MS purity 99%, MS ESI calcd. forC₂₈H₄₀N₃[M−2H₂O+H]+418.3 found 418.3. SFC 97% de.

EXAMPLES 36 & 37: Synthesis of1-((S)-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-13-methyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methoxypropyl)-1H-pyrazole-4-carbonitrile(36) &1-((R)-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-13-methyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methoxypropyl)-1H-pyrazole-4-carbonitrile(37)

Synthesis of 36.1

To a solution of 2,6-di-tert-butyl-4-methylphenol (24 g, 108 mmol) intoluene (30 mL) under N₂ at 0° C. was added AlMe₃ (2 M in toluene, 27mL, 54 mmol) dropwise. After stirring at 25° C. for 1 h, to the MAD (54mmol in 30 mL toluene) solution was added a solution of 36.0 (5 g, 18.2mmol) in toluene (20 mL) dropwise at −60° C. After stirring at −60° C.for 1 h under N₂, n-prMgBr (27.3 mL, 54.6 mmol, 2M in THF) was addeddropwise at −60° C. After stirring at −60° C. for another 4 h, thereaction mixture was poured into aqueous citric acid (100 mL, sat.) at10° C. and extracted with EtOAc (2×100 mL). The combined organic layerwas dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum.The residue was purified by silica gel chromatography (PE/EtOAc=0-20% togive 36.1 (3.83 g, 66.1%). ¹H NMR (400 MHz, CDCl3) δ_(H) 2.49-2.37 (m,1H), 2.31-1.98 (m, 2H), 1.97-1.87 (m, 1H), 1.86-1.73 (m, 4H), 1.72-1.60(m, 2H), 1.55-1.45 (m, 5H), 1.45-1.27 (m, 10H), 1.27-1.00 (m, 4H), 0.93(t, J=7.2 Hz, 3H), 0.87 (s, 3H).

Synthesis of 36.2

To a mixture of EtPPh₃Br (26.5 g, 71.4 mmol) in THF (50 mL) was addedt-BuOK (8.01 g, 71.4 mmol) at 15° C. under N₂. After stirring at 50° C.for 30 min, 36.1 (3.8 g, 11.9 mmol) was added in portions below 40° C.After stirring at 40° C. for 1 h, the reaction mixture was quenched with10% NH₄Cl aqueous (100 mL) at 15° C. and extracted with EtOAc (500 mL).The combined organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by trituration withMeOH/H₂O (1:1, 300 mL) at reflux to give 36.2 (4.5 g). ¹H NMR (400 MHz,CDCl3) δ_(H) 5.10 (d, J=7.2 Hz, 1H), 2.41-2.09 (m, 4H), 1.78-1.71 (m,3H), 1.66-1.63 (m, 3H), 1.56-1.51 (m, 3H), 1.50-1.42 (m, 3H), 1.37-1.29(m, 6H), 1.21-1.00 (m, 6H), 0.93 (t, J=7.28 Hz, 3H), 0.87 (s, 3H).

Synthesis of 36.3

To a solution of 36.2 (4.5 g, 13.6 mmol) in THE (50 mL) was added 9-BBNdimer (9.95 g, 40.8 mmol) at 15° C. After stirring at 40° C. for 1 h,the mixture was sequentially treated with EtOH (7.9 mL, 135 mmol) at 15°C., NaOH (27 mL, 5M, 135 mmol) at −10° C., and H₂02 (13.5 mL, 10 M, 135mmol) dropwise. After stirring at 80° C. for 1 h, the reaction wasquenched with sat. Na₂S₂O₃ (50 mL), stirred for 30 mins and extractedwith EtOAc (100 mL). The combined organic phase was washed withsaturated brine (2×100 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by silica gelchromatography (PE/EtOAc=10 to 20%) to give 36.3 (3.2 g, 67.5%). ¹H NMR(400 MHz, CDCl3) δ_(H) 3.74-3.66 (m, 1H), 1.85-1.60 (m, 10H), 1.49-1.29(m, 13H), 1.22 (d, J=6 Hz, 3H), 1.16-1.00 (m, 7H), 0.93 (t, J=7.2 Hz,3H), 0.66 (s, 3H).LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₃H₄₀O₂[M+H−2H₂O]⁺ 313.3, found 313.3.

Synthesis of 36.4

To a solution of 36.3 (3.1 g, 8.89 mmol) in DCM (30 mL) was addedDess-martin (7.5 g, 17.7 mmol) at 25° C. After stirring at 25° C. for 10mins, the mixture was quenched by NaHCO₃/Na₂S₂O₃ aqueous (1:1, 375 mL)at 25° C. The organic phase was separated and washed with NaHCO₃/Na₂S₂O₃aqueous (1:1, 375 mL), brine (200 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under vacuum to give 36.4 (4 g). ¹H NMR (400MHz, CDCl3) δ_(H) 2.40 (d, J=12.80 Hz, 1H), 2.11 (s, 3H), 1.93-1.81 (m,4H), 1.72-1.63 (m, 8H), 1.50-1.41 (m, 8H), 1.13-1.02 (m, 6H), 0.94-0.91(m, 3H), 0.62 (s, 3H).

Synthesis of 36.5

To a mixture of MePPh₃Br (12.3 g, 34.5 mmol) in THE (50 mL) was addedt-BuOK (3.87 g, 34.5 mmol) at 15° C. under N₂. After stirring at 50° C.for 30 min, 36.4 (4 g, 11.5 mmol) was added in portions below 50° C.After stirring at 50° C. for 1 h, the reaction mixture was quenched with10% NH4Cl aqueous (100 mL) at 15° C. and extracted with EtOAc (200 mL).The combined organic phase was dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by silica gelchromatography (PE/EtOAc=0 to 5%) to give 36.5 (600 mg, 15.1%). ¹H NMR(400 MHz, CDCl3) δ_(H) 4.84 (s, 1H), 4.69 (s, 1H) 2.04-1.99 (m, 2H),1.86-1.76 (m, 3H), 1.75 (s, 3H), 1.74-1.57 (m, 6H), 1.56-1.50 (m, 2H),1.49-1.28 (m, 10H), 1.23-0.97 (m, 6H), 0.93 (t, J=7.2 Hz, 3H), 0.56 (s,3H).

Synthesis of 36.6

To a solution of 36.5 (1.7 g, 4.93 mmol) and 2, 6-dimethylpyridine (1.57g, 14.7 mmol) in DCM (10 mL) was added TBSOTf (1.56 g, 5.91 mmol) at 0°C. After stirring at 25° C. for 16 h, the mixture was poured into water(20 mL) and extracted with EtOAc (2×50 mL). The combined organic phasewas washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash column (100% of PE) togive 36.6 (2 g, 88.4%).

Synthesis of 36.7

To a solution of 36.6 (2 g, 4.35 mmol) in DCM (50 mL) was added m-CPBA(1.31 g, 6.52 mmol, 85%) at 25° C. After stirring at 25° C. for 2 h, themixture was poured into NaHCO₃ aqueous (100 mL, sat.) and extracted withEtOAc (2×100 mL). The combined organic phase was washed with brine(2×100 mL), dried over Na₂SO₄, filtered and concentrated to give 36.7(1.8 g). ¹H NMR (400 MHz, CDCl₃) δ_(H) 2.96-2.86 (m, 0.7H), 2.62-2.54(m, 0.7H), 2.52-2.48 (m, 0.3H), 2.52-2.47 (m, 0.3H), 2.34-2.29 (m, 1H),2.10-1.91 (m, 2H), 1.81-1.58 (m, 7H), 1.52-1.34 (m, 11H), 1.32-0.96 (m,13H), 0.86 (d, J=1.2 Hz, 9H), 0.83-0.75 (m, 1H), 0.68 (s, 2H), 0.07 (s,6H).

Synthesis of 36.8 & 36.8a

To a solution of 36.7 (900 mg, 1.89 mmol) in DMF (10 mL) were addedCs₂CO₃ (1.48 g, 5.67 mmol) and 1H-pyrazole-4-carbontrile (527 mg, 5.67mmol). After stirring at 130° C. for 16 h, the mixture was added intoNH₄Cl (100 mL, sat.) and extracted with EtOAc (3×100 mL). The combinedorganic layer was washed with water (100 mL), brine (100 mL), dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was purified byflash column (0-15% of EtOAc in PE) to give product (780 mg). Theresidue was purified by flash column (0-10% of EtOAc in PE) to give 36.8(350 mg) and 36.8a (230 mg).

36.8: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.92 (s, 1H), 7.84-7.80 (m, 1H),4.37 (d, J=13.6 Hz, 1H), 4.09 (d, J=13.6 Hz, 1H), 2.48 (s, 1H),2.08-1.96 (m, 1H), 1.83-1.58 (m, 8H), 1.49-1.21 (m, 16H), 1.20-1.01 (m,6H), 0.96 (s, 3H), 0.92 (s, 3H), 0.86 (s, 14H), 0.07 (s, 6H).

36.8a: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.92 (s, 1H), 7.89 (s, 1H),4.22-4.11 (m, 1H), 4.06-3.95 (m, 1H), 2.26 (s, 1H), 2.14-2.02 (m, 1H),1.95-1.87 (m, 1H), 1.81-1.61 (m, 7H), 1.50-1.24 (m, 18H), 1.20-0.99 (m,10H), 0.91-0.87 (m, 9H), 0.07 (d, J=1.2 Hz, 6H).

Synthesis of 36.9

To a solution of 36.8 (350 mg, 0.6162 mmol) in THE (10 mL) was added NaH(123 mg, 3.08 mmol, 60%) at 0° C. under N₂. After stirring for 0.5 h,MeI (874 mg, 6.16 mmol) was added into the reaction mixture at 25° C.After stirring at 25° C. for another 16 h, the reaction mixture wasquenched by ammonia (1 mL), poured into water (50 mL) and extracted withEtOAc (2×50 mL). The combined organic phase was washed with brine (2×50mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residuewas purified by flash column (0-20% of EtOAc in PE) to give 36.9 (350mg). ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.91 (s, 1H), 7.75 (s, 1H), 4.34-4.18(m, 2H), 3.18 (s, 3H), 2.00-1.93 (m, 1H), 1.83-1.58 (m, 11H), 1.48-1.25(m, 19H), 1.22-0.97 (m, 15H), 0.86 (s, 22H), 0.07 (s, 6H).

Synthesis of 36.9a

To a solution of 36.8a (230 mg, 0.4049 mmol) in THE (5 mL) was added NaH(80.6 mg, 2.02 mmol, 60%) at 0° C. under N₂. After stirring for 0.5 h,MeI (573 mg, 4.04 mmol) was added into the reaction mixture at 25° C.After stirring at 25° C. for another 16 h, the reaction mixture wasquenched by ammonia (1 mL), poured into water (50 mL) and extracted withEtOAc (2×50 mL). The combined organic phase was washed with brine (2×50mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residuewas purified by flash column (0-20% of EtOAc in PE) to give 36.9a (230mg). ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.90 (s, 1H), 4.35-4.03 (m, 3H),3.21-3.05 (m, 3H), 2.11-1.94 (m, 3H), 1.80-1.61 (m, 11H), 1.47-1.27 (m,18H), 1.21-0.98 (m, 18H), 0.86-0.73 (m, 16H), 0.07 (br s, 6H)

Synthesis of 36

To a solution of 36.9 (350 mg, 0.5993 mmol) in THE (3.5 mL) was addedTBAF (5.99 mL, 5.99 mmol, 1M in THF). After stirring at 80° C. for 16 h,the reaction mixture was quenched with NH₄Cl solution (30 mL, sat.) andextracted with EtOAc (2×20 mL). The combined organic phase was washedwith brine (50 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to the product (120 mg). The product (130 mg, 0.2779 mmol)was purified by SFC (Column: DAICEL CHIRALPAK AD-H (250 mm*30 mm, 5 um);Condition: 0.1%/% NH₃H₂O IPA; Begin B 35 End B 35; Flow Rate (ml/min)60) to give 36 (95.4 mg, 73.9%, Rt=1.459 min). ¹H NMR (400 MHz, CDCl₃)δ_(H) 7.99-7.86 (m, 1H), 7.80-7.67 (m, 1H), 4.35-4.13 (m, 2H), 3.25-3.12(m, 3H), 1.95 (br d, J=12.8 Hz, 1H), 1.83-1.57 (m, 9H), 1.49-1.23 (m,12H), 1.07 (s, 10H), 0.93 (t, J=7.2 Hz, 3H), 0.85 (s, 3H). LC-ELSD/MSpurity 99%, MS ESI calcd for C₂₈H₄₁N₃[M-CH₃OH—H₂O+H]⁺ 418.3, found418.3. SFC 99% de.

Synthesis of 37

To a solution of 36.9a (230 mg, 0.3938 mmol) in THE (2.3 mL) was addedTBAF (1.96 mL, 1.96 mmol, 1M in THF). After stirring at 80° C. for 16 h,the reaction mixture was quenched with NH₄Cl solution (30 mL, sat.) andextracted with EtOAc (2×20 mL). The combined organic phase was washedwith brine (50 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to give the product (50 mg). The product was purified bySFC (Column: DAICEL CHIRALPAK AD-H (250 mm*30 mm, 5 um); Condition: 0.1%NH₃H₂O IPA; Begin B 35 End B 35; Flow Rate (ml/min) 60) to afford 37(39.2 mg, 78.5%, Rt=1.703 min). ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.90 (s,1H), 7.75 (s, 1H), 4.24 (s, 2H), 3.14 (s, 3H), 2.04 (br d, J=12.4 Hz,1H), 1.84-1.59 (m, 9H), 1.49-1.05 (m, 18H), 1.02 (s, 4H), 0.93 (t, J=7.2Hz, 3H), 0.82 (s, 3H). LC-ELSD/MS purity 99%, MS ESI calcd forC₂₈H₄₁N₃[M-CH₃OH—H₂O+H]⁺ 418.3, found 418.3. SFC 99% de.

EXAMPLE 38: Synthesis of1-(2,2-difluoro-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl)-1H-pyrazole-4-carbonitrile(38)

Synthesis of 38.1

To a solution of 38.0 (1.70 g, 4.87 mmol) in MeOH (20 ml) were added HBr(196 mg, 974 μmol, 40% in water) and Br₂ (934 mg, 5.84 mmol) at 25° C.After stirring at 25° C. for 2 h, the mixture was quenched by NaHCO₃ (10mL, sat.aq.), treated with water (20 mL), and extracted with EtOAc (2×30mL). The combined organic phase was washed with brine (30 mL), driedover anhydrous Na₂SO₄, filtered and concentrated in vacuum to afford38.1 (2.1 g), which was used directly for the next step. ¹H NMR (400MHz, CDCl₃) δ_(H) 3.96-3.86 (m, 2H), 3.43-3.34 (m, 6H), 2.85-2.76 (m,1H), 2.62 (s, 1H), 2.22-2.11 (m, 1H), 1.95-1.87 (m, 1H), 1.86-1.67 (m,7H), 1.58-1.33 (m, 9H), 1.21-0.97 (m, 4H), 0.63 (s, 3H).

Synthesis of 38.2

To a solution of 38.1 (2.1 g, 4.91 mmol) in acetone (30 mL) were added1H-pyrazole-4-carbonitrile (685 mg, 7.36 mmol) and K₂CO₃ (2.02 g, 14.7mmol). After stirring at 15° C. for 12 h, the mixture was treated withwater (30 mL) and extracted with EtOAc (2×30 mL). The combined organicphase was washed with brine (30 mL), dried over anhydrous Na₂SO₄,filtered and concentrated. The residue was purified by flash column(0˜50% of EtOAc in PE) to give 38.2 (1.6 g, 74.4%). ¹H NMR (400 MHz,CDCl₃) δ_(H) 7.85 (s, 1H), 7.81 (s, 1H), 5.05-4.86 (m, 2H), 3.44-3.38(m, 5H), 2.67-2.56 (m, 2H), 2.25-2.14 (m, 1H), 2.07-2.02 (m, 1H),1.87-1.72 (m, 6H), 1.67-1.59 (m, 2H), 1.53-1.34 (m, 8H), 1.31-1.26 (m,2H), 1.18-1.05 (m, 3H), 0.67 (s, 3H).

Synthesis of 38.3

To a solution of 38.2(1.6 g, 3.63 mmol) in DCM (30 mL) were added DMAP(442 mg, 3.63 mmol) and acetyl acetate (1.47 g, 14.5 mmol). Afterstirring at 25° C. for 16 h, the mixture was poured into ice-water (100mL), stirred for 10 mins. and extracted with DCM (2×50 mL). The combinedorganic phase was washed with brine (2×100 mL), dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was purified by flashcolumn (0-20% of EtOAc in PE) to give 38.3 (590 mg, 33.9%). ¹H NMR (400MHz, CDCl3) δ_(H) 7.85 (s, 1H), 7.81 (s, 1H), 5.04-4.86 (m, 2H),3.86-3.74 (m, 2H), 3.40-3.34 (m, 4H), 2.55-2.66 (m, 1H), 2.25-2.15 (m,2H), 2.03-1.98 (m, 4H), 1.90-1.68 (m, 10H), 1.56-1.49 (m, 2H), 1.44-1.31(m, 6H), 1.15-0.98 (m, 4H), 0.67 (s, 3H).

Synthesis of 38.4

To a solution of 38.3 (290 mg, 600 μmol) in chloroform (4 mL) was addeddropwise DAST (1.58 ml, 12 mmol, 1.22 g/ml) at 0° C. under N₂. Afterstirring at 60° C. for 12 h, the mixture was quenched with NaHCO₃ (30mL) carefully and extracted with EtOAc (2×30 mL). The combined organicphase was washed with brine (20 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by flash column (0-30% of EtOAcin PE) to give 38.4 (34 mg, 11.2%). ¹H NMR (400 MHz, CDCl3) δ_(H) 7.92(s, 1H), 7.82 (s, 1H), 4.50-4.37 (m, 1H), 3.84-3.75 (m, 2H), 3.36 (s,3H), 2.02-1.93 (m, 5H), 1.86-1.63 (m, 8H), 1.53-1.26 (m, 7H), 1.24-1.00(m, 7H), 0.86 (m, 4H).

Synthesis of 38

To a solution of 38.4 (24 mg, 47.6 μmol) in MeOH (1 ml) was addedLiOH(1.99 ml, 9.99 mmol, 5M) at 15° C. After stirring at 15° C. for 20h, the mixture was poured into water (20 mL), stirred for 10 min, andextracted with EtOAc (3×5 mL). The combined organic phase was washedwith brine (2×5 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash column (0˜30% of EtOAcin PE) to give 38 (10 mg). ¹H NMR (400 MHz, CDCl3) δ_(H) 7.92 (s, 1H),7.83 (s, 1H), 4.52-4.37 (m, 2H), 3.42-3.36 (m, 5H), 2.58 (s, 1H),2.02-1.96 (m, 1H), 1.83-1.67 (m, 8H), 1.50-1.34 (m, 7H), 1.25 (s, 3H),1.15-1.06 (m, 5H), 0.86 (d, J=3.0 Hz, 3H). LC-ELSD/MS 30-90AB_2 min_E,purity>99%, MS ESI calcd. for C₂₆H₃₇F₂N₃O₂[M−H₂O+H]⁺ 444.2, found 444.2.

EXAMPLE 39: Synthesis of1-((1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)cyclopropyl)methyl)-1H-pyrazole-4-carbonitrile(39)

Synthesis of 39.1

To a suspension of NaH (2.75 g, 60% in oil, 68.8 mmol) in THE (60 mL)was added (EtO)₂P (0) CH₂COOEt (15.4 g, 68.8 mmol) dropwise at 0° C.After stirring at 20° C. for 10 min, a solution of 39.0 (10 g, 34.4mmol) in THE (20 mL) was added dropwise at 20° C. After refluxing at 70°C. for 16 h, the mixture was poured into NH₄Cl (200 mL, 10% aq.) andextracted with EtOAc (200 mL). The combined organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was purified byflash column (0˜20% of EtOAc in PE) to give 39.1 (12 g, 97%). ¹H NMR(400 MHz, CDCl₃) δ_(H) 5.52 (t, J=2.4 Hz, 1H), 4.15 (q, J=7.2 Hz, 2H),2.90-2.75 (m, 2H), 1.95-1.60 (m, 5H), 1.50-1.25 (m, 18H), 1.20-1.05 (m,4H), 0.82 (s, 3H).

Synthesis of 39.2

To a solution of 39.1 (12 g, 33.2 mmol) in THE (150 mL) was added Pd/C(2 g, dry, 10%) under N₂. The mixture was degassed under vacuum andpurged with H₂ three times. After stirring under H₂ (40 psi) at 40° C.for 24 h, the mixture was filtered through a pad of celite and washedwith THF (3×50 mL). The combined filtrate was concentrated to give 39.2(11.7 g, 97.5%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 4.11 (q, J=6.8 Hz, 2H),2.35 (dd, J=5.2, 14.4 Hz, 1H), 2.10 (dd, J=10.0, 14.8 Hz, 1H), 2.00-1.75(m, 6H), 1.55.1.50 (m, 3H), 1.50-1.35 (m, 6H), 1.35-1.25 (m, 10H),1.20-0.95 (m, 6H), 0.59 (s, 3H).

Synthesis of 39.3

To a suspension of LiAlH₄ (6.0 g, 158 mmol) in THF (120 mL) was added asolution of 39.2 (11.1 g, 30.6 mmol) in THF (30 mL) at 0° C. under N₂.After stirring at 0° C. for 10 min, to the mixture was added water/THF(6 mL/200 mL) dropwise followed by NaOH (6 mL, 10% aq.) and water (18mL). The mixture was filtered, and the precipitate was washed with THF(3×100 mL). The combined filtrate was concentrated and triturated fromDCM (50 mL) to give 39.3 (9 g, 92%). ¹H NMR (400 MHz, CDCl₃) δ_(H)3.75-3.55 (m, 2H), 1.90-1.60 (m, 9H), 1.50-1.15 (m, 16H) 1.15-0.90 (m,6H), 0.59 (s, 3H).

Synthesis of 39.4

To a solution of 39.3 (3 g, 9.3 mmol) in DCM (80 mL) was added DMP (7.92g, 18.7 mmol). After stirring at 30° C. for 1 h, the mixture was washedwith a mixed solution of NaHCO₃ (160 mL, aq. sat.) and Na₂S₂O₃ (80 mL,aq. sat.) twice, dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by flash column (10˜30% of EtOAc in PE) to give39.4 (2.2 g, 74%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 9.76 (t, J=2.4 Hz, 1H),2.55-2.45 (m, 1H), 2.30-2.20 (m, 1H), 2.00-1.80 (m, 5H), 1.55.1.55 (m,4H), 1.50-1.20 (m, 13H), 1.30-1.00 (m, 6H), 0.60 (s, 3H).

Synthesis of 39.5

A solution of 39.4 (2 g, 6.27 mmol), HCHO (5.05 g, 37%, 62.6 mmol), Et₃N(1.90 g, 18.8 mmol) in water (10 mL) and dioxane (20 mL) was stirred at70° C. for 16 hs. The mixture was added into water (50 mL) and extractedwith EtOAc (3×20 mL). The combined organic layer was washed with brine(50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated to give39.5 (1.5 g). ¹H NMR (400 MHz, CDCl₃) δ_(H) 9.55 (s, 1H), 6.27 (s, 1H),6.11 (s, 1H), 2.85-2.75 (m, 1H), 1.90-1.59 (m, 9H), 1.52-1.28 (m, 11H),1.26 (s, 3H), 1.20-0.85 (m, 4H), 0.52 (s, 3H).

Synthesis of 39.6

To a mixture of 39.5 (1.5 g, 4.53 mmol) and 2-methyl-2-butene (10 mL) inacetone (50 mL) were added a solution of NaClO₂ (2.04 g, 22.6 mmol) andNaH₂PO₄ (2.71 g, 22.6 mmol) in H₂O (25 mL) at 0° C. After stirring at20° C. for 16 h, the reaction mixture was diluted with H₂O (100 mL) andextracted with EtOAc (3×50 mL). The combined organic phase was washedwith brine (20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to give 39.6 (1.9 g). ¹H NMR (400 MHz, CDCl₃) δ_(H) 6.38(s, 1H), 5.64 (s, 1H), 2.81 (t, J=9.2 Hz, 1H), 1.90-1.59 (m, 10H),1.52-1.28 (m, 9H), 1.26 (s, 3H), 1.24-0.90 (m, 6H), 0.55 (s, 3H).

Synthesis of 39.7

To a solution of 39.6 (1.9 g, 5.48 mmol) in DMF (30 mL) was added K₂CO₃(1.52 g, 10.9 mmol) at 20° C. After stirring at 20° C. for 1 h, MeI(1.16 g, 8.22 mmol) was added at 20° C. After stirring at 20° C. foranother 2 h, the mixture was added into NH₄Cl (150 mL, sat.) andextracted with EtOAc (3×50 mL). The combined organic layer was washedwith water (2×100 mL), brine (150 mL), dried over anhydrous Na₂SO₄,filtered and concentrated. The residue was purified by flash column(0-15% of EtOAc in PE) to give 39.7 (1.26 g, 64%). ¹H NMR (400 MHz,CDCl₃) δ_(H) 6.19 (s, 1H), 5.50 (s, 1H), 3.73 (s, 3H), 2.80 (t, J=9.2Hz, 1H), 1.90-1.59 (m, 8H), 1.52-1.28 (m, 11H), 1.26 (s, 3H), 1.24-0.90(m, 5H), 0.52 (s, 3H).

Synthesis of 39.8

To a solution of 39.7 (1.25 g, 3.46 mmol) in DMF (30 mL) were addedMe₃SI (2.10 g, 10.3 mmol) and t-BuOK (1.15 g, 10.3 mmol). After stirringat 20° C. for 16 h, the mixture was added into water (200 mL) andextracted with EtOAc (3×50 mL). The combined organic layer was washedwith brine (200 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash column (0-15% of EtOAcin PE) to give 39.8 (350 mg, 27%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 3.63(s, 3H), 2.45-2.35 (m, 1H), 1.92-1.78 (m, 3H), 1.75-1.59 (m, 5H),1.52-1.28 (m, 9H), 1.26 (s, 3H), 1.25-0.80 (m, 9H), 0.68-0.55 (m, 5H).LC-ELSD/MS 30-90AB_2 min_E, purity 99%, MS ESI calcd. forC₂₄H₃₇O₂[M−H₂O+H]⁺ 357.3, found 357.3.

Synthesis of 39.9

To a solution of 39.8 (350 mg, 0.93 mmol) in THE (10 mL) was addedLiAlH₄ (70.5 mg, 1.86 mmol) at 20° C. After stirring at 20° C. for 1 h,water (70 mg) was added to the mixture. The mixture was filtered, andthe mother liquid was concentrated to give 39.9 (320 mg, 99%). ¹H NMR(400 MHz, CDCl₃) δ_(H) 3.96 (d, J=10.8 Hz, 1H), 3.00 (d, J=11.2 Hz, 1H),2.10-2.00 (m, 2H), 1.92-1.75 (m, 3H), 1.74-1.59 (m, 3H), 1.52-1.28 (m,11H), 1.26 (s, 3H), 1.25-0.95 (m, 7H), 0.72 (s, 3H), 0.71-0.65 (m, 1H),0.35-0.25 (m, 2H), 0.24-0.11 (m, 1H).sLC-ELSD/MS purity 99%, MS ESIcalcd. for C₂₃H₃₅ [M−2H₂O+H]⁺ 311.3, found 311.3.

Synthesis of 39.10

To a solution of 39.9 (1.7 g, 4.90 mmol) in DCM (50 mL) were addedsilica gel (2.10 g) and PCC (2.10 g, 9.80 mmol) at 25° C. After stirringat 25° C. for 1 h, the mixture was concentrated. The residue waspurified by flash column (0-20% of EtOAc in PE) to give 39.10 (1.28 g,76.1%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 9.48 (s, 1H), 2.01 (t, J=8 Hz,1H), 1.72-1.87 (m, 5H), 1.62-1.69 (m, 5H), 1.36-1.50 (m, 8H), 1.26 (s,4H), 0.91-1.17 (m, 8H), 0.79-0.84 (m, 1H), 0.68 (s, 3H).

Synthesis of 39.11

To a solution of 39.10 (1.28 g, 3.71 mmol) in EtOH (30 mL) was addedNH₂NH₂H₂O (1.11 g, 22.2 mmol) and Et₃N (749 mg, 7.42 mmol) at 25° C.After stirring at 75° C. for 5 h, the mixture was added into water (50mL) and extracted with EtOAc (3×30 mL). The combined organic layer waswashed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to give 39.11 (1.3 g). ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.32(s, 1H), 1.77-1.81 (m, 4H), 1.56-1.66 (m, 12H), 1.35-1.42 (m, 6H),1.00-1.11 (m, 9H), 0.68 (s, 4H), 0.60-0.63 (m, 1H), 0.49-0.54 (m, 1H).

Synthesis of 39.12

To a solution of 39.11 (1.3 g, 3.62 mmol) in MeOH (20 mL) was addedNaCNBH₃ (2.27 g, 36.2 mmol) at 25° C. After stirring at 70° C. for 16 h,the mixture was added into water (100 mL) and extracted with EtOAc (3×30mL). The combined organic layer was washed with brine (100 mL), driedover anhydrous Na₂SO₄, filtered and concentrated to give 39.12 (1.5 g).¹H NMR (400 MHz, CDCl₃) δ_(H) 2.51-2.99 (m, 4H), 2.28-2.40 (m, 1H), 2.04(s, 3H), 1.80 (br s, 3H), 1.53-1.72 (m, 4H), 1.29-1.50 (m, 8H),0.98-1.15 (m, 5H), 0.97-1.18 (m, 5H), 0.74-0.92 (m, 4H), 0.72 (s, 1H),0.44 (br s, 2H), 0.07 (s, 4H).

Synthesis of 39.13

To a solution of 39.12 (350 mg, 970 μmol) in EtOH (5 mL) were added Et₃N(979 mg, 9.70 mmol) and 2-(ethoxymethylidene) propanedinitrile (236 mg,1.94 mmol). After stirring at 75° C. for 16 h, the mixture was addedinto water (30 mL) and extracted with EtOAc (3×20 mL). The combinedorganic layer was washed with brine (2×50 mL), dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was purified by flashcolumn (20-40% of EtOAc in PE) to give 39.13 (85 mg). ¹H NMR (400 MHz,CDCl₃) δ_(H) 7.46 (s, 1H), 4.27 (s, 2H), 3.93-3.97 (m, 1H), 1.92-2.00(m, 2H), 1.77-1.80 (m, 5H), 1.38-1.42 (m, 9H), 1.04-1.11 (m, 10H), 0.78(s, 3H), 0.55.0.74 (m, 3H), 0.59 (s, 1H), 0.39-0.43 (m, 2H), 0.10-0.13(m, 1H).

Synthesis of 39

To a solution of 39.13 (50 mg, 114 μmol) in THE (2 mL) was added -BuONO(25 mg, 242 μmol). After stirring at 70° C. for 16 h, the mixture wasadded into water (20 mL) and extracted with EtOAc (3×20 mL). Thecombined organic layer was washed with brine (50 mL), dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was purified byflash column (15-30% of EtOAc in PE) to give 39 (4.4 mg, 3.23%). ¹H NMR(400 MHz, CDCl₃) δ_(H) 7.94 (s, 1H), 7.79 (s, 1H), 4.69 (d, J=12.0 Hz,1H), 3.54 (d, J=12.0 Hz, 1H), 1.97-2.02 (m, 1H), 1.65-1.87 (m, 7H),1.34-1.47 (m, 8H), 1.25 (s, 5H), 0.98-1.12 (m, 7H), 0.87-0.90 (m, 1H),0.76 (s, 3H), 0.46-0.55 (m, 2H), 0.36-0.42 (m, 1H). LC-ELSD/MSpurity>99%, MS ESI calcd. For C₂₇H₃₉N₃O [M−H₂O+H]⁺ 404.3, found 404.3.

EXAMPLE 40: Synthesis of1-((3-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)oxetan-3-yl)methyl)-1H-pyrazole-4-carbonitrile(40)

Synthesis of 40.1

To a suspension of NaH (2.23 g, 56.0 mmol, 60% in oil) in THE (50 mL)was added (EtO)₂P(O)CH₂COOEt (12.5 g, 56.0 mmol) dropwise at 0° C. Afterstirring at 20° C. for 10 min, a solution of 40.0 (9 g, 28.0 mmol) inTHE (90 mL) was added dropwise at 20° C. After refluxing at 70° C. for16 h, the mixture was poured into 10% NH₄C₁ (200 mL, aq.) and extractedwith EtOAc (200 mL×3). The organic layer was washed with brine (100mL×2), dried over Na₂SO₄, filtered and concentrated. The residue waspurified by flash column (0˜20% of EtOAc in PE) to give 40.1 (9.5 g,87.1%). ¹H NMR (400 MHz, CDCl₃)) δ_(H) 5.46-5.57 (m, 1H), 3.86-4.40 (m,3H), 3.27-3.51 (m, 5H), 2.71-2.97 (m, 2H), 2.53-2.62 (m, 1H), 1.61-1.95(m, 7H), 1.34-1.53 (m, 6H), 1.32-1.09 (m, 10H), 0.81 (s, 3H).

Synthesis of 40.2

To a solution of 40.1 (9.5 g, 24.3 mmol) in THE (100 mL) was added Pd/C(1.5 g, dry, 10%) under N₂. The suspension was degassed under vacuum andpurged with H₂ for three times. After stirring under H₂ (40 psi) at 40°C. for 24 h, the mixture was filtered through a pad of celite and washedwith THE (3×100 mL). The combined filtrate was concentrated to give 40.2(9.3 g, 97.5%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 4.00-4.25 (m, 2H), 3.39(s, 4H), 3.31-3.46 (m, 1H), 2.58 (s, 1H), 2.29-2.40 (m, 1H), 2.03-2.15(m, 1H), 1.60-1.94 (m, 9H), 1.28-1.58 (m, 8H), 1.27-1.23 (m, 4H),0.97-1.17 (m, 6H), 0.59 (s, 3H).

Synthesis of 40.3

To a solution of i-Pr₂NH (7.16 g, 70.8 mmol) in THE (60 mL) was addedn-BuLi (28.3 mL, 2.5 M in hexane, 70.8 mmol) at −70° C. To the mixturewas added a solution of 40.2 (9.3 g, 23.6 mmol) in THE (90 mL) at −70°C. After stirring at −70° C. for 1 h, to the mixture was added ClCOOEt(7.68 g, 70.8 mmol). After stirring at −70° C. for 1 h, the mixture wasquenched by NH₄Cl (200 mL, 10%) and extracted with EtOAc (3×150 mL). Thecombined organic layer was washed with brine (2×100 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue waspurified by flash column (0˜40% of EtOAc in PE) twice to give 40.3 (9.2g). ¹H NMR (400 MHz, CDCl₃) δ_(H) 4.11-4.19 (m, 4H), 3.34-3.45 (m, 5H),3.32-3.24 (m, 1H), 2.57 (s, 1H), 2.13-2.27 (m, 1H), 1.86-2.00 (m, 1H),1.61-1.85 (m, 5H), 1.31-1.57 (m, 8H), 1.23-1.29 (m, 8H), 0.82-1.20 (m,7H), 0.70 (s, 3H).

Synthesis of 40.4

To a suspension of t-BuOK (11.1 g, 99.0 mmol) in THE (110 mL) was addeda solution of 40.3 (9.2 g, 19.8 mmol) in THE (90 mL) at 0° C. Afterstirring at 20° C. for 1 h, BOMCI (18.4 g, 118 mmol) was added at 0° C.After stirring at 0° C. for 1 h, the mixture was poured into NH₄Cl (250mL, sat.) and extracted with EtOAc (100 mL×3). The combined organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated to give40.4 (20.7 g).

Synthesis of 40.5

To a suspension of LAH (7.51 g, 198 mmol) in THE (200 mL) was added asolution of 40.4 (11.5 g, 19.8 mmol) in THF (100 mL) dropwise at 0° C.After stirring at 0° C. for 1 h, the mixture was quenched sequentiallywith water/THF (7.5 mL/150 mL), NaOH (7.5 mL, 10%) and water (22.5 mL).The mixture was filtered and the solid was washed with THE (3×100 mL).The combined filtrate was concentrated to 150 mL and HCl (2 M, 40 mL)was added. After stirring at 50° C. for 1 h, to the mixture was addedNaHCO₃ (200 mL, sat) and extracted with EtOAc (150 mL×3). The combinedorganic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by flash column (30˜100% of EtOAc in PE) twice togive 40.5 (4.8 g). ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.27-7.40 (m, 5H), 4.50(s, 2H), 3.59-3.97 (m, 6H), 3.38 (s, 5H), 2.53-2.81 (m, 3H), 1.66-1.94(m, 5H), 1.29-1.61 (m, 12H), 0.85-1.23 (m, 7H), 0.73 (s, 3H).

Synthesis of 40.6

To a solution of 40.5 (1 g, 1.99 mmol) in THE (20 mL) was added n-BuLi(0.952 mL, 2.5 M in hexane, 2.38 mmol) at 0° C. After stirring at 0° C.for 10 min, to the mixture was added a solution of TsCl (453 mg, 2.38mmol) in THE (5 mL). After stirring at 0° C. for 1 h, to the mixture wasadded n-BuLi (952 μL, 2.5 M in hexane, 2.38 mmol) at 0° C. Afterstirring at 15° C. for 2 h, the mixture was quenched by NH₄Cl (20 mL,sat.) and extracted with EtOAc (2×30 mL). The combined organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. Theresidue was purified by flash column (0˜15% of EtOAc in PE) to give 40.6(600 mg, 62.5%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.27-7.41 (m, 5H),4.78-4.88 (m, 1H), 4.41-4.67 (m, 4H), 4.20-4.27 (m, 1H), 3.85-3.94 (m,1H), 3.61-3.71 (m, 1H), 3.39 (s, 5H), 2.59 (s, 1H), 2.05-2.17 (m, 1H),1.58.1.99 (m, 7H), 0.95-1.50 (m, 16H), 0.51 (s, 3H).

Synthesis of 40.7

To a solution of 40.6 (550 mg, 1.13 mmol) in THE (20 mL) was added Pd/C(0.5 g, 10%, wet) under N₂. The mixture was degassed under vacuum andpurged with H₂ for three times. After stirring under H₂ (40 psi) at 30°C. for 20 h, the mixture was filtered and the solid was washed with THF(20 mL). The combined filtrate was concentrated and purified by flashcolumn (40˜70% of EtOAc in PE) to give 40.7 (300 mg, 67.7%). ¹H NMR (400MHz, CDCl₃) δ_(H) 4.85 (d, J=6.4 Hz, 1H), 4.55 (d, J=6.0 Hz, 1H), 4.46(d, J=6.0 Hz, 1H), 4.24 (d, J=6.8 Hz, 1H), 4.09 (dd, J=6.4, 10.8 Hz,1H), 3.82 (dd, J=4.8, 11.2 Hz, 1H), 3.39 (s, 5H), 2.59 (s, 1H),2.04-2.21 (m, 1H), 1.59-2.02 (m, 10H), 0.98-1.50 (m, 14H), 0.53 (s,3H).LC-ELSD/MS purity: 99%, MS ESI calcd. for C₂₄H₄₀O₄[M+H]⁺ 393.2,found C₂₄H₄₀O₄[M+H]⁺ 393.3.

Synthesis of 40.8

To a solution of 40.7 (150 mg, 0.3820 mmol) in DCM (5 mL) were addedN-Me-imidazole (31.3 mg, 0.382 mmol), TEA (193 mg, 1.91 mmol) and TsCl(217 mg, 1.14 mmol). After stirring at 20° C. for 1 h, the mixture wasconcentrated to give 40.8 (340 mg).

Synthesis of 40

To a solution of 40.8 (250 mg, 0.4572 mmol) in DMF (5 mL) were added4-cyano-pyrazole (85.1 mg, 0.9144 mmol), KI (75.8 mg, 0.4572 mmol) andK₂CO₃ (128 mg, 0.9144 mmol). After stirring at 80° C. for 16 h, themixture was washed with water (5 mL) and extracted with EtOAc (50 mL×3).The combined organic layer was washed with brine (30 mL×2), dried overanhydrous Na₂SO₄, filtered and concentrated under vacuum. The residuewas purified by Pre-HPLC (column: Welch Xtimate C18 150*25 mm*5 um;Mobile phase: A: CO₂ B: water (0.225% FA)-ACN; gradient: from 55% to 85%of B, Flow Rate (ml/min): 25) to give 40 (10 mg, 3.44%). ¹H NMR (400MHz, CDCl₃) δ_(H) 7.88 (s, 1H), 7.84 (s, 1H), 4.70-4.55 (d, J=6.8 Hz,1H), 4.56-4.70 (m, 2H), 4.55-4.45 (m, 2H), 4.38-4.28 (m, 1H), 3.39 (s,5H), 2.57 (s, 1H), 1.60-2.15 (m, 11H), 0.98-1.50 (m, 13H), 0.69 (s,3H).LC-ELSD/MS purity: 99%, MS ESI calcd. for C₂₈H₄₁N₃O₃ [M+H]⁺ 468.3,found C₂₈H₄₁N₃O₃ [M+H]⁺ 468.3.

EXAMPLE 41: Synthesis of1-(2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylpropyl)-1H-pyrazole-4-carbonitrile(41)

Synthesis of 41.1

To a suspension of NaH (2.75 g, 60%, 68.8 mmol) in THE (60 mL) was added(EtO)₂P(O)CH₂COOEt (15.4 g, 68.8 mmol) dropwise at 0° C. under N₂. Afterstirring at 20° C. for 10 mins, a solution of 41.0 (10 g, 34.4 mmol) inTHE (20 mL) was added dropwise at 20° C. After refluxing at 70° C. for16 h, the mixture was poured into NH₄Cl (200 mL, 10% aq) and extractedwith EtOAc (200 mL). The organic layer was separated, dried over Na₂SO₄,filtered, concentrated. The residue was purified by flash column (0˜20%EtOAc in PE) to give 41.1 (12 g, 97%). ¹H NMR (400 MHz, CDCl₃) δ_(H)5.52 (t, J=2.4 Hz, 1H), 4.15 (q, J=7.2 Hz, 2H), 2.90-2.75 (m, 2H),1.95-1.60 (m, 5H), 1.50-1.25 (m, 18H), 1.20-1.05 (m, 4H), 0.82 (s, 3H).

Synthesis of 41.2

To a solution of 41.1 (12 g, 33.2 mmol) in THE (150 mL) was added Pd/C(2 g, dry, 10%) at 20° C. under N₂. After stirring at 40° C. under H₂(40 psi) for 24 h, the mixture was filtered though a pad of celite andwashed with THF (3×50 mL). The combined filtrate was concentrated togive 41.2 (11.7 g, 97.5%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 4.11 (q, J=6.8Hz, 2H), 2.35 (dd, J=5.2, 14.4 Hz, 1H), 2.10 (dd, J=10.0, 14.8 Hz, 1H),2.00-1.75 (m, 6H), 1.70-1.50 (m, 3H), 1.50-1.35 (m, 6H), 1.35-1.25 (m,10H), 1.20-0.95 (m, 6H), 0.59 (s, 3H).

Synthesis of 41.3

To a solution of 41.2 (2.3 g, 6.3 mmol), 2,6-dimethylpyridine (1.69 g,15.8 mmol) in DCM (20 mL) was added dropwise tert-butyldimethylsilyltrifluoromethanesulfonate (3.33 g, 12.6 mmol) at 0° C. After stirring at15° C. for 18 h, the reaction mixture was quenched with water (30 mL)and extracted with DCM (2×20 mL). The combined organic phase washed withbrine (50 mL), dried over Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by flash column (0˜10% of EtOAc in PE)to afford 41.3 (2.9 g). ¹H NMR (400 MHz, CDCl₃) δ_(H) 4.14-4.08 (m, 2H),2.40-2.32 (m, 1H), 2.15-2.03 (m, 1H), 1.95-1.59 (m, 9H), 1.46-1.28 (m,6H), 1.27-1.21 (m, 8H), 1.20-0.92 (m, 7H), 0.86-0.85 (m, 9H), 0.59 (s,3H), 0.09-0.05 (m, 6H)

Synthesis of 41.4

To a solution of i-Pr₂NH (2.34 g, 23.2 mmol) in THE (20 mL) was addedn-BuLi (11.1 mL, 2.5 M, 27.8 mmol) at −70° C. under N₂. The mixture waswarmed to 0° C. and stirred at 0° C. for 30 mins. To the mixture wasadded to a stirred solution of 41.3 (3.7 g, 7.7 mmol) in THE (20 mL) at−70° C. After stirring at −70° C. for 1 h, methyl iodide (6.60 g, 46.5mmol) was added. After stirring at 20° C. for 16 h, the reaction wasdiluted with water (50 mL) and extracted with EtOAc (3×30 mL). Thecombined organic layers were washed with brine (100 mL), dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was purified byflash column (0-5% of EtOAc in PE) to give 41.4 (2.7 g, 71%). ¹H NMR(400 MHz, CDCl₃) δ_(H) 4.20-4.11 (m, 2H), 2.36-2.26 (m, 1H), 1.90-1.56(m, 10H), 1.51-1.29 (m, 8H), 1.28-1.27 (m, 3H), 1.21 (s, 3H), 1.10 (d,J=6.8 Hz, 3H), 1.07-0.87 (m, 6H), 0.86 (s, 9H), 0.69 (s, 3H), 0.06 (s,6H)

Synthesis of 41.5

To a solution of i-Pr₂NH (1.15 g, 11.4 mmol) in THE (10 mL) under N₂ wasadded n-BuLi (5.4 mL, 2.5 M, 13.6 mmol) at −70° C. The mixture waswarmed to 0° C. and stirred at 0° C. for 30 min. To the mixture wasadded to a stirred solution of 41.4 (2.8 g, 5.7 mmol) in THF (10 mL) at−78° C. After stirring at −0° C. for 1 h, methyl iodide (4.85 g, 34.2mmol) was added. After stirring at 20° C. for 16 h, the reaction wasdiluted with water (20 mL) and extracted with EtOAc (3×30 mL). Thecombined organic layers were washed with brine (50 mL), dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was purified byflash column (0-5% of EtOAc in PE) to give 41.5 (1.7 g). ¹H NMR (400MHz, CDCl₃) δ_(H) 4.19-3.98 (m, 1H), 1.80-1.58 (m, 9H), 1.45-1.29 (m,9H), 1.23-1.18 (m, 8H), 1.13-0.89 (m, 11H), 0.86 (s, 9H), 0.72-0.58 (m,3H), 0.08-0.06 (m, 6H)

Synthesis of 41.6

To the mixture of 41.5 (1.7 g, 3.4 mmol) in THE (10 mL) was added TBAF(6.7 ml, 1 M, 6.7 mmol). After stirring at 80° C. for 18 h, the mixturecooled to 20° C., diluted with water (10 mL), and extracted with EtOAc(3×20 mL). The combined organic phase was washed with brine (2×30 mL),dried over anhydrous Na₂SO₄, filtered, concentrated. The residue waspurified by flash column (0˜30% of EtOAc in PE) to give 41.6 (870 mg).¹H NMR (400 MHz, CDCl₃) δ_(H) 4.09-3.99 (m, 1H), 1.80-1.61 (m, 9H),1.48-1.29 (m, 11H), 1.26-1.24 (m, 4H), 1.19 (d, J=5.6 Hz, 3H), 1.15-0.90(m, 10H), 0.83 (d, J=7.2 Hz, 1H), 0.72-0.58 (m, 3H)

Synthesis of 41.7

To a solution of 41.6 (870 mg, 2.3 mmol) in THE (20 mL) was added LiAlH₄(175 mg, 4.6 mmol) at 25° C. After stirring at 25° C. for 16 h, thereaction was quenched with H₂O (0.2 ml) and then HCl (50 mL, 1 M). Themixture was poured into water (30 mL), stirred for 5 min and filtered.The filter cake was washed with water (2×20 mL) and dried to give 41.7(240 mg, 30%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 3.42-3.28 (m, 2H),2.01-1.95 (m, 1H), 1.87-1.78 (m, 3H), 1.64-1.57 (m, 4H), 1.52-1.26 (m,12H), 1.26 (s, 3H), 1.25-1.19 (m, 2H), 1.11-1.01 (m, 4H), 0.99 (s, 3H),0.90 (s, 3H), 0.77 (s, 3H). LC-ELSD/MS: purity >99%; MS ESI calcd. forC₂₃H₄₀O₂ [M−H₂O+H]⁺331.3, found 331.3, MS ESI calcd. for C₂₃H₄₀O₂[M−H₂O−H₂O+H]⁺313.3, found 313.3,

Synthesis of 41.8

To a solution of 41.7 (100 mg, 0.3 mmol) in DCM (3 mL) were addedN-methylimidazole (35.3 mg, 0.4 mmol), TEA (87.0 mg, 0.8 mmol) and TsCl(164 mg, 0.8 mmol). After stirring at 25° C. for 2 h, the mixture waspoured into water (20 mL) and extracted with EtOAc (2×30 mL). Thecombined organic phase was washed with water (2×20 mL), dried overanhydrous Na₂SO₄, filtered and concentrated a 41.8 (200 mg). ¹H NMR (400MHz, CDCl₃) δ_(H) 7.79 (d, J=8.0 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H),3.79-3.66 (m, 2H), 2.46 (s, 3H), 1.85-1.77 (m, 4H), 1.66-1.49 (m, 5H),1.45-1.27 (m, 9H), 1.26 (s, 3H), 1.23-0.99 (m, 7H), 0.97 (s, 3H), 0.88(s, 3H), 0.70 (s, 3H)

Synthesis of 41

To a solution of 41.8 (200 mg, 0.4 mmol) in DMF (5 mL) were added1H-pyrazole-4-carbonitrile (55.5 mg, 0.6 mmol) and Cs₂CO₃ (645 mg, 2.0mmol) at 25° C. under N₂. After stirring at 120° C. for 16 h, themixture was added into water (20 mL), stirred at 25° C. for 5 mins andextracted with EtOAc (3×30 mL). The combined organic layer was washedwith brine (2×100 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash column (0-40% of EtOAcin PE) to give 41 (130 mg).

41 (130 mg) was further purified by HPLC (Method: SAGE-TJF-242-P1A;Column: Welch Xtimate C18 150*25 mm*5 um; Condition: water(0.04%/NH₃H₂O)-ACN; Begin B: 70; End B: 100) to afford 41 (15.2 mg,12%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.78 (s, 1H), 7.74 (s, 1H), 4.09 (d,J=13.6 Hz, 1H), 3.92 (d, J=13.6 Hz, 1H), 2.00-1.94 (m, 1H), 1.87-1.56(m, 9H), 1.52-1.29 (m, 9H), 1.26 (s, 3H), 1.23-1.02 (m, 6H), 0.99 (s,3H), 0.94 (s, 3H), 0.82 (s, 3H). LC-ELSD/MS: purity >99%; MS ESI calcd.for C₂₇H₄₁N₃O [M−H₂O+H]⁺ 406.4, found 406.4. MS ESI calcd. for C₂₇H₄₁N₃O[M+H]⁺ 424.4, found 424.4.

EXAMPLE 42 & 43: Synthesis of1-((S)-2-((3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile(42) &1-((R)-2-((3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile(43)

Synthesis of 42.1

To a stirred solution of trimethylsulfonium iodide (6.44 g, 31.6 mmol)in DMSO (40 mL) and THF (20 mL) was added NaH (1.26 g, 31.6 mmol, 60%).After stirring at 0° C. for 1.0 h under N₂, the mixture was added to asolution of 42.0 (8 g, 26.4 mmol) in DMSO (20 mL) at 0° C. Afterstirring at 25° C. for 16 h, the reaction was treated with water (100mL) and extracted with EtOAc (2×100 mL). The combined organic phase waswashed with water (2×100 mL), brine (200 mL), dried over anhydrousNa₂SO₄, filtered, and concentrated in vacuum. The residue was purifiedby column (5%-30% of EtOAc in PE) to give 42.1 (5 g). ¹H NMR (400 MHz,CDCl₃) δ_(H) 2.63-2.57 (m, 2H), 2.48-2.33 (m, 2H), 2.13-1.51 (m, 10H),1.51-0.94 (m, 11H), 0.94-0.80 (m, 7H).

Synthesis of 42.2 & 42.2A

To a solution of 42.1 (6.9 g, 21.8 mmol) in MeOH (50 mL) was addedCH₃ONa (11.7 g, 218 mmol). After stirring at 65° C. for 16 h, thereaction mixture was quenched by addition of H₂O (100 mL) and extractedwith EtOAc (3×100 mL). The combined organic phase was washed with brine(200 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. Theresidue was purified by column (2˜30% of EtOAc in PE) to give 42.2 (3.7g, 49%) and 42.2A (2 g, 26%).

42.2: ¹H NMR (400 MHz, CDCl₃) δ_(H) 3.40-3.34 (m, 5H), 2.59 (s, 1H),2.46-2.39 (m, 1H), 2.12-1.52 (m, 13H), 1.52-1.14 (m, 10H), 0.84-0.77 (m,6H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₂H₃₃O [M+H−2H₂O]⁺ 313.2,found 313.2.

42.2A: ¹H NMR (400 MHz, CDCl₃) δ_(H) 3.38 (s, 3H), 3.22-3.17 (m, 2H),2.47-2.40 (m, 2H), 2.10-1.57 (m, 10H), 1.57-1.48 (m, 3H), 1.48-1.06 (m,10H), 0.87-0.83 (m, 6H). LC-ELSD/MS purity 99%, MS ESI calcd. forC₂₂H₃₃O [M+H−2H₂O]⁺ 313.2, found 313.2.

Synthesis of 42.3

To a suspension of Ph₃PEtBr (10.8 g, 29.2 mmol) in anhydrous THE (100mL) was added t-BuOK (3.27 g, 29.2 mmol) at 25° C. under N₂. Afterstirring at 60° C. for 30 mins, a solution of 42.2 (3.4 g, 9.75 mmol) inanhydrous THE (50 mL) was added. After stirring at 60° C. for 16 h, themixture was poured into saturated NH₄Cl (100 mL) and extracted withEtOAc (2×100 mL). The combine organic phase was washed with brine (200mL), filtered and concentrated. The residue was purified by column (0˜3%of EtOAc in PE) to give 42.3 (3.5 g). ¹H NMR (400 MHz, CDCl₃) δ_(H)5.12-4.98 (m, 1H), 3.41-3.34 (m, 5H), 2.58 (s, 1H), 2.39-2.09 (m, 3H),1.96-1.52 (m, 10H), 1.52-1.31 (m, 6H), 1.31-1.03 (m, 8H), 0.84-0.70 (m,6H).

Synthesis of 42.4

To a solution of 42.3 (3.5 g, 9.71 mmol) in anhydrous THE (50 mL) wasadded 9-BBN dimer (7.04 g, 29.1 mmol) at 25° C. under N₂. After stirringat 60° C. for 16 h, the mixture was cooled and sequentially treated at0° C. with EtOH (20 mL) and NaOH (9.7 mL, 5M, 48.5 mmol) dropwise. Afteraddition, H₂O₂(9.7 mL, 97.1 mmol, 10 M in water) was added slowly untilthe inner temperature no longer rises and the inner temperature wasmaintained below 30° C. The mixture was stirred at 60° C. for 2 h. Thenthe mixture was cooled and quenched with Na₂S₂O₃ (100 mL, sat. aq.). Themixture was extracted with EtOAc (2×100 mL) and the organic layer wasdried over Na₂SO₄, filtered and concentrated in vacuum. The residue waspurified by column (20% of EtOAc in PE) to give 42.4 (2.2 g). ¹H NMR(400 MHz, CDCl₃) δ_(H) 3.72-3.58 (m, 1H), 3.41-3.34 (m, 4H), 2.59 (s,1H), 2.03-1.46 (m, 16H), 1.46-1.02 (m, 16H), 0.79-0.63 (m, 4H).

Synthesis of 42.5

To a solution of 42.4 (2.1 g, 5.54 mmol) in DCM (30 mL) was added DMP(4.66 g, 11 mmol). After stirring at 25° C. for 1 h, the mixture wasquenched with NaHCO₃ (50 mL) and extracted with EtOAc (3×30 mL). Thecombined organic layer was washed with Na₂S₂O₃ (3×30 mL, sat.), brine(50 mL), dried over Na₂SO₄, filtered and concentrated in vacuum to give42.5 (2.1 g). ¹H NMR (400 MHz, CDCl₃) δ_(H) 3.40-3.34 (m, 5H), 2.67-2.50(m, 2H), 2.04-1.59 (m, 10H), 1.59-1.32 (m, 7H), 1.32-1.08 (m, 10H), 0.77(t, J=7.6 Hz, 3H), 0.58 (s, 3H).

Synthesis of 42.6

To a suspension of MePh₃BrP (6.93 g, 19.4 mmol) in anhydrous THE (50 mL)was added t-BuOK (2.17 g, 19.4 mmol) at 25° C. under N₂. After stirringat 60° C. for 30 mins, a solution of 42.5 (2.1 g, 5.57 mmol) inanhydrous THE (20 mL) was added at 25° C. After stirring at 60° C. for16 h, the mixture was poured into saturated NH₄Cl (50 mL) and extractedwith EtOAc (2×100 mL). The combined organic phase was washed with brine(200 mL), filtered and concentrated. The residue was purified by column(0˜10% of EtOAc in PE) to give 42.6 (1.1 g, 53%). ¹H NMR (400 MHz,CDCl₃) δ_(H) 4.83 (s, 1H), 4.69 (s, 1H), 3.41-3.34 (m, 5H), 2.58 (s,1H), 2.04-1.55 (m, 8H), 1.55-1.30 (m, 10H), 1.30-1.07 (m, 10H), 0.77 (t,J=7.2 Hz, 3H), 0.54 (s, 3H).

Synthesis of 42.7

To a solution of 42.6 (400 mg, 1.06 mmol) in DCM (10 mL) was addedm-CPBA (454 mg, 2.12 mmol, 80%) at 25° C. After stirring at 25° C. for 1h, the mixture was quenched with sat. NaHCO₃ and Na₂S₂O₃ (40 mL,v:v=1:1) and extracted with DCM (2×20 mL). The combined organic phasewas washed with sat. NaHCO₃ and Na₂S₂O₃ (100 mL, v:v=1:1), dried overNa₂SO₄, filtered and concentrated to give 42.7 (430 mg). ¹H NMR (400MHz, CDCl₃) δ_(H) 3.40-3.34 (m, 5H), 2.88 (d, J=4.4 Hz, 0.6 H),2.62-2.47 (m, 2H), 2.31 (d, J=4.8 Hz, 0.4 H), 2.04-1.55 (m, 9H),1.55-1.29 (m, 10H), 1.29-0.99 (m, 10H), 0.77 (t, J=7.6 Hz, 3H), 0.65 (s,2H).

Synthesis of 42.8

To a solution of 42.7 (430 mg, 1.1 mmol) in DMF (5 mL) were added Cs₂CO₃(1.07 g, 3.3 mmol) and 1H-pyrazole-4-carbonitrile (255 mg, 2.75 mmol).After stirring at 120° C. for 48 h, the mixture was added into saturatedNH₄Cl (50 mL) and extracted with EtOAc (3×50 mL). The combined organiclayer was washed with LiCl (100 mL, 5% in water), brine (2×100 mL),dried over anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by column (10˜30% of EtOAc in PE) to afford 42.8 (410 mg).

Separation of 42 & 43

42.8 was separated by SFC (Column: DAICEL CHIRALPAK AD-H (250 mm×30 mm,5 um), Condition: 0.1% NH₃H₂O, ETOH, Begin B: 45%, End B: 45%) to give42 (201.7 mg, 92%, Rt=2.165 min) and 43 (100 mg, Rt=5.035 min). 43 (100mg) was further purified by HPLC separation (column: Xtimate C18 150×25mm×5 um, condition: water (0.225% FA)-ACN, Begin B: 90, End B: 100) togive 43 (53.4 mg, 53.4%, Rt=5.016 min).

42: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.92 (s, 1H), 7.82 (s, 1H), 4.35-4.05(m, 2H), 3.40-3.34 (m, 5H), 2.61-2.53 (m, 2H), 2.02-1.57 (m, 10H),1.57-1.18 (m, 10H), 1.18-0.75 (m, 14H). LC-ELSD/MS purity 99%, MS ESIcalcd. for C₂₉H₄₂N₃O [M+H-H₂O]⁺ 448.3, found 448.3. analytic SFC 100%de.

43: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.88 (s, 1H), 7.79 (s, 1H), 4.17-3.98(m, 2H), 3.40-3.34 (m, 5H), 2.62 (s, 1H), 2.34 (s, 1H), 2.07-1.59 (m,10H), 1.59-1.14 (m, 13H), 1.14-1.03 (m, 5H), 0.84-0.75 (m, 6H).LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₉H₄₂N₃O [M+H-H₂O]⁺ 448.3,found 448.3. analytic SFC 100% de.

Example 44 & 45: Synthesis of1-((S)-2-((3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-13-methyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile(44) &1-((R)-2-((3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-13-methyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile(45)

Synthesis of 44.1

To a solution of 44.0 (400 mg, 1.02 mmol) in DMF (10 mL) were added1H-pyrazole-4-carbonitrile (237 mg, 2.55 mmol) and Cs₂CO₃(1.66 g, 5.10mmol) at 20° C. under N₂. After stirring at 120° C. for 16 h, thereaction mixture was poured into water (20 mL) and extracted with ethylacetate (3×50 mL). The combined organic layers were washed with 5% LiCl(3×100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by flash column (0˜15% of EtOAc in PE)to give 44.1 (600 mg).

Separation of 44 & 45

44.1 (600 mg, 1.24 mmol) was separated by SFC (Column: DAICEL CHIRALCELOD (250 mm*30 mm, 10 um; Condition: 0.1% NH₃H₂O ETOH; Begin B: 55; EndB: 55; FlowRate(ml/min): 80) to give 44 (233.8 mg, Rt=0.641 min) and 45(107.5 mg, Rt=1.929 min).

44: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.92 (s, 1H), 7.81 (s, 1H), 4.35-4.31(m, 1H), 4.08-4.05 (m, 1H), 2.52 (s, 1H), 2.04-1.97 (m, 1H), 1.90-1.57(m, 10H), 1.57-1.30 (m, 10H), 1.30-1.00 (m, 9H), 1.00-0.85 (m, 9H), 0.78(t, J=7.6 Hz, 3H). LC-ELSD/MS purity 99%, MS ESI calcd. forC₃₀H₄₄N₃[M+H−2H₂O]⁺ 446.3, found 446.3. SFC 100% de.

45: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.88 (s, 1H), 7.80 (s, 1H), 4.17-4.13(m, 1H), 4.02-3.99 (m, 1H), 2.30 (s, 1H), 2.07-2.00 (m, 1H), 1.94-1.52(m, 10H), 1.52-1.23 (m, 13H), 1.23-1.02 (m, 9H), 0.94 (t, J=7.2 Hz, 3H),0.85 (s, 3H), 0.78 (t, J=7.6 Hz, 3H). LC-ELSD/MS purity 99%, MS ESIcalcd. for C₃₀H₄₄N₃[M+H−2H₂O]⁺ 446.3, found 446.4. SFC 100% de.

EXAMPLE 46 & 47: Synthesis of1-((R)-2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile(46) &1-((S)-2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile(47)

Synthesis of 46.1

To a solution of t-BuOK (6.17 g, 55.0 mmol) in THF (150 mL) was added46.0 (8 g, 27.5 mmol) at 25° C. under N₂. After stirring at 25° C. for10 min, methyl benzenesulfinate (8.59 g, 55.0 mmol) was added. Afterstirring at 30° C. for another 30 min, the mixture was quenched with H₂O(200 mL) and extracted with EtOAc (200×3 mL). The organic layer wasdried over Na₂SO₄, filtered and concentrated in vacuum to give 46.1 (16g). ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.74-7.44 (m, 8H), 3.53-3.44 (m, 1H),3.26 (dd, J=8.2, 9.9 Hz, 1H), 2.41-2.35 (m, 1H), 1.81 (br s, 1H),1.56-1.30 (m, 15H), 1.23-1.01 (m, 4H), 0.98 (s, 1H), 0.93 (s, 2H).

Synthesis of 46.2

To a mixture of 46.1 (16 g, 38.5 mmol) in xylene (200 mL) was addedNa₂CO₃ (61.1 g, 577 mmol) in portions. After stirring at 140° C. underN₂ for 12 h, the mixture was filtered and concentrated. The residue waspurified by flash column (0˜15% of EtOAc in PE) to give 46.2 (4.3 g). ¹HNMR (400 MHz, CDCl₃) δ_(H) 7.55-7.51 (m, 1H), 6.03 (dd, J=3.1, 5.9 Hz,1H), 2.37 (br d, J=10.3 Hz, 1H), 1.85 (br s, 5H), 1.72 (br s, 2H),1.62-1.34 (m, 9H), 1.33-1.23 (m, 6H), 1.08 (s, 3H).

Synthesis of 46.3

To a solution of bromo (cyclopropyl) magnesium (6.14 g, 84.6 ml, 42.3mmol, 0.5 M in THF) in THF (150 mL) was added CuI (8.05 g, 42.3 mmol) at0° C. under N₂. After stirring at 0° C. for 1 h, 46.2 (3.5 g, 12.1 mmol)was added. After stirring at 0° C. for another 3 h, the residue waspoured into NH₄Cl (50 mL) and extracted with EtOAc (3×50 mL). Thecombined organic phase was washed with brine (2×50 mL), dried overanhydrous Na₂SO₄, filtered, concentrated. The residue was purified byflash column (0˜30% of EtOAc in PE) to give 46.3 (3.8 g). ¹H NMR (400MHz, CDCl₃) δ_(H) 2.47-2.39 (m, 1H), 2.38-2.27 (m, 1H), 1.96-1.69 (m,8H), 1.63-1.48 (m, 6H), 1.45-1.43 (m, 1H), 1.40-1.31 (m, 3H), 1.30-1.27(m, 4H), 1.26-1.18 (m, 1H), 1.11 (s, 4H), 0.95 (br d, J=8.3 Hz, 1H),0.70-0.62 (m, 1H), 0.47 (s, 1H), 0.24-0.03 (m, 2H). LC-ELSD/MS purity99%, MS ESI calcd. for C₂₂H₃₃N₃O [M−H₂O+H]⁺ 313.3, found 313.3.

Synthesis of 46.4

To a mixture of EtPPh₃Br (20.6 g, 55.5 mmol) in THF (100 mL) was addedt-BuOK (6.22 g, 55.5 mmol) at 25° C. under N₂. After stirring at 45° C.for 30 min, 46.3 (3.7 g, 11.1 mmol) was added below 45° C. Afterstirring at 45° C. for another 16 h, the reaction mixture was quenchedwith 10% NH₄Cl aqueous (40 mL) at 25° C. and extracted with EtOAc (2×30mL). The combined organic phase was dried over Na₂SO₄, filtered,concentrated. The residue was purified by flash column (0˜20% of EtOAcin PE) to give 46.4 (3.7 g). ¹H NMR (400 MHz, CDCl₃) δ_(H) 5.18-5.07 (m,1H), 2.46-2.36 (m, 1H), 2.31-2.15 (m, 2H), 1.84 (br d, J=6.8 Hz, 4H),1.77-1.63 (m, 4H), 1.59-1.30 (m, 12H), 1.29-1.27 (m, 4H), 1.19-1.08 (m,5H), 0.86-0.77 (m, 1H), 0.58-0.49 (m, 1H), 0.40-0.31 (m, 1H), 0.13-0.00(m, 2H).

Synthesis of 46.5

To a solution of 46.4 (700 mg, 2.04 mmol) in anhydrous THE (15 mL) wasadded BH₃.Me₂S (1.01 ml, 10.2 mmol) at 25° C. under N₂. After stirringat 25° C. for 12 h, the resulting mixture was treated sequentially withethanol (3.09 mL, 61.2 mmol) at 25° C., NaOH aqueous (12.2 mL, 5.0 M,61.2 mmol) and H₂O₂(6.13 mL, 30% in water, 61.2 mmol) dropwise at 0° C.After stirring at 50° C. for 1 h, the mixture was cooled, poured intoNa₂S₂O₃ (50 mL, sat. aq.) and extracted with EtOAc (2×50 mL). Thecombined organic phase was washed with brine (30 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue waspurified by flash column (15˜25% of EtOAc in PE) to give 46.5 (560 mg).¹H NMR (400 MHz, CDCl₃) δ_(H) 3.82-3.74 (m, 1H), 2.24 (td, J=9.2, 13.5Hz, 1H), 2.02 (s, 1H), 1.85 (br d, J=6.5 Hz, 5H), 1.92-1.58 (m, 1H),1.92-1.58 (m, 1H), 1.41 (br d, J=3.3 Hz, 9H), 1.28 (s, 5H), 1.24 (d,J=6.3 Hz, 4H), 1.18-1.01 (m, 4H), 0.92-0.78 (m, 4H), 0.57 (br dd, J=3.9,7.7 Hz, 1H), 0.42-0.32 (m, 1H), 0.16-0.02 (m, 2H). LC-ELSD/MS purity99%, MS ESI calcd. for C₂₄H₃₇ [M−2H₂O+H]⁺ 325.3, found 325.3.

Synthesis of 46.6

To a mixture of 46.5 (460 mg, 1.27 mmol) in DCM (30 mL) was added DMP(1.61 g, 3.81 mmol) in portions. After stirring at 20° C. for 30 min,the mixture was quenched with NaHCO₃ (20 mL) and Na₂S₂O₃(20 mL) andextracted with DCM (2×30 mL) The organic phase was washed with Na₂S₂O₃(2×20 mL, sat.), brine (30 mL, sat), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by flash column (0˜15% of EtOAcin PE) to give 46.6 (310 mg). ¹H NMR (400 MHz, CDCl₃) δ_(H) 2.44 (dd,J=8.8, 10.5 Hz, 1H), 2.14 (s, 4H), 2.02-1.92 (m, 3H), 1.85 (br d, J=6.8Hz, 2H), 1.76-1.65 (m, 2H), 1.38 (br s, 12H), 1.29 (s, 4H), 1.17-1.04(m, 2H), 0.87-0.77 (m, 1H), 0.85 (s, 3H), 0.62-0.52 (m, 1H), 0.46-0.35(m, 1H), 0.17-0.01 (m, 2H). LC-ELSD/MS purity 99%, MS ESI calcd. forC₂₄H₃₇O [M−H₂O+H]⁺ 341.3, found 341.3.

Synthesis of 46.7

To a suspension of Ph₃PMeBr (3.08 g, 8.64 mmol) in THF (20 mL) was addedt-BuOK (969 mg, 8.64 mmol) at 20° C. under N₂. After stirring for 30 minat 50° C., a solution of 46.6 (310 mg, 0.864 mmol) in THE (5 mL) wasadded dropwise to the resulting suspension. After stirring at 50° C. for2 h under N₂, the reaction mixture was poured into 10% NH₄Cl (50 mL) andextracted with EtOAc (40 mL×3). The combined organic phase was washedwith brine (40 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash column (0˜10% of EtOAcin PE) to give 46.7 (300 mg). ¹H NMR (400 MHz, CDCl₃) δ_(H) 4.86 (s,1H), 4.74 (s, 1H), 2.03-1.79 (m, 7H), 1.78 (s, 3H), 1.76-1.60 (m, 3H),1.51-1.27 (m, 13H), 1.23-0.98 (m, 4H), 0.78 (s, 4H), 0.58 (br s, 1H),0.45-0.32 (m, 1H), 0.17-0.03 (m, 1H), 0.17-0.03 (m, 1H).

Synthesis of 46.8

To a solution of 46.7 (200 mg, 0.560 mmol) in DCM (20 mL) was addedm-CPBA (223 mg, 1.11 mmol, 85%) at 0° C. After stirring at 0° C. for 1 hto give colorless suspension, the mixture was quenched with NaHCO₃ andNa₂S₂O₃ (40 mL, v:v=1:1, sat.) and extracted with DCM (2×40 mL). Thecombined organic phase was washed with NaHCO₃ and Na₂S₂O₃ (60 mL,v:v=1:1, sat.), dried over Na₂SO₄, filtered and concentrated to give46.8 (250 mg). ¹H NMR (400 MHz, CDCl₃) δ_(H) 3.01-2.62 (m, 1H),2.59-2.30 (m, 1H), 2.03-1.60 (m, 3H), 1.51-1.34 (m, 12H), 1.33-1.24 (m,10H), 1.16-1.04 (m, 3H), 1.01 (s, 1H), 0.95-0.72 (m, 4H), 0.61-0.51 (m,1H), 0.41-0.30 (m, 1H), 0.14-0.06 (m, 3H).

Synthesis of 46.9

To solution of 46.8 (250 mg, 0.670 mmol) in DMF (5 mL) were added Cs₂CO₃(655 mg, 2.01 mmol) and 1H-pyrazole-4-carbonitrile (155 mg, 1.67 mmol).After stirring at 130° C. for 12 h, the mixture was added into saturatedNH₄Cl (50 mL) and extracted with EtOAc (3×20 mL). The combined organiclayer was washed with LiCl (50 mL, 5% in water), brine (2×20 mL), driedover anhydrous Na₂SO₄, filtered, concentrated and purified by column(0˜30% of EtOAc in PE) to afford 46.9 (300 mg).

Separation of 46 & 47

46.9 was separated by SFC (Column: DAICEL CHIRALCEL OD-H (250 mm*30 mm,5 um); Condition:0.1% NH₃H₂O ETOH; Begin B:35%; End B:35%) to afford 46(24.4 mg, 7.82%, Rt=1.708 min) and 47 (83.7 mg, 26.8%, Rt=1.847 min).

46: ¹H NMR (400 MHz, CDCl3) δ_(H) 7.92 (s, 1H), 7.81 (s, 1H), 4.28-3.97(m, 1H), 4.28-3.97 (m, 1H), 2.30 (s, 1H), 1.84 (br d, J=6.5 Hz, 7H),1.76-1.60 (m, 2H), 1.40 (br d, J=4.8 Hz, 9H), 1.32-1.23 (m, 6H),1.22-1.16 (m, 1H), 1.09 (d, J=1.5 Hz, 8H), 0.90-0.78 (m, 1H), 0.65-0.55(m, 1H), 0.46-0.36 (m, 1H), 0.19-0.02 (m, 2H). LC-ELSD/MS purity 99%, MSESI calcd. for C₂₉H₄₀N₃ [M−2H₂O+H]⁺430.3, found 430.3. SFC 100% de

47: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.94 (s, 1H), 7.83 (s, 1H), 4.37-4.06(m, 2H), 2.59 (s, 1H), 2.01 (br d, J=12.0 Hz, 3H), 1.84 (br d, J=6.8 Hz,6H), 1.52-1.33 (m, 8H), 1.32-1.14 (m, 9H), 1.12 (s, 3H), 1.03 (s, 4H),0.89-0.79 (m, 1H), 0.64-0.55 (m, 1H), 0.46-0.35 (m, 1H), 0.19-0.03 (m,2H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₉H₄₀N₃ [M−2H₂O+H]+430.3,found 430.3. SFC 99% de.

EXAMPLE 48 & 49: Synthesis of1-((S)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile(48) &1-((R)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile(49)

Synthesis of 48.1

To a solution of MeMgBr (2.3 mL, 6.92 mmol, 3M) in THE (10 mL) was addedCuI (988 mg, 5.19 mmol) at 0° C. After stirring at 0° C. for 1 h, 46.2(500 mg, 1.73 mmol) in THF (5 mL) was added at 0° C. After stirring at0° C. for 3 h, the mixture was poured into saturated NH₄Cl (20 mL) andextracted with EtOAc (3×30 mL). The combined organic layer was washedwith brine (20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash column (10%˜25% of EtOAcin PE) to give 48.1 (360 mg, 68.4%, 35.2 mg). ¹H NMR (400 MHz, CDCl₃)δ_(H) 2.51-2.39 (m, 2H), 2.29-2.19 (m, 1H), 1.91-1.80 (m, 3H), 1.78-1.62(m, 4.5H), 1.53-1.46 (m, 2.5H), 1.44-1.31 (m, 7H), 1.28 (s, 5H),1.24-1.20 (m, 1H), 1.10 (d, J=7.6 Hz, 3H), 1.03 (s, 3H). LC-ELSD/MSpurity 99%, MS ESI calcd. for C₂₀H₃₁O [M−H₂O+H]⁺287.2, found 287.2.

Synthesis of 48.2

To a mixture of EtPPh₃Br (18.2 g, 49.2 mmol) in THF (40 mL) was addedt-BuOK (5.52 g, 49.2 mmol) at 20° C. under N₂. After stirring at 40° C.for 30 min, 48.1 (2.5 g, 8.21 mmol) in THE (30 mL) was added in portionsbelow 40° C. After stirring at 40° C. for 16 h, the reaction mixture wasquenched with 10% NH₄Cl aqueous (200 mL) at 15° C. and extracted withEtOAc (3×200 mL). The combined organic phase was washed with brine(2×150 mL), filtered, concentrated under vacuum. The residue waspurified by flash column (0˜30% ethyl acetate in PE) to give 48.2 (3.1g). ¹H NMR (400 MHz, CDCl₃) δ_(H) 5.18-5.07 (m, 1H), 2.63-2.50 (m, 1H),2.33-2.23 (m, 3H), 2.22-2.06 (m, 3H), 1.91-1.79 (m, 3H), 1.66 (s, 7H),1.61-1.31 (m, 11H), 1.25-1.13 (m, 7H), 1.09 (s, 3H), 0.93 (m, 3H).

Synthesis of 48.3

To a solution of 48.2 (2.6 g, 8.21 mmol) in anhydrous THE (30 mL) wasadded 9-BBN dimer (4.00 g, 16.4 mmol) at 25° C. under N₂. After stirringat 40° C. for 16 h, to the resulting mixture was added ethanol (4.53 g,98.5 mmol) at 25° C., followed by NaOH aqueous (19.7 mL, 5.0 M, 98.5mmol) and H₂O₂(9.85 mL, 10 M, 98.5 mmol) dropwise at 0° C. Afterstirring at 80° C. for 1 h, the mixture was cooled, poured into Na₂S₂O₃(100 mL, sat. aq.) and extracted with EtOAc (2×150 mL). The organicphase was washed with brine (2×100 mL), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuum. The residue was purified by flashcolumn (15˜40% EtOAc in PE) to give 48.3 (2.6 g, 94.8%) ¹H NMR (400 MHz,CDCl₃) δ_(H) 3.86-3.65 (m, 1H), 2.38-2.26 (m, 1H), 2.20-2.07 (m, 1H),1.91-1.52 (m, 11H), 1.50-1.37 (m, 6H), 1.29-1.24 (m, 8H), 1.19-0.98 (m,5H), 0.93 (m, 3H), 0.82 (s, 3H).

Synthesis of 48.4

To a solution of 48.3 (2.6 g, 7.77 mmol) in DCM (30 mL) was addedDess-martin (6.57 g, 15.5 mmol) at 25° C. After stirring at 25° C. for10 min, the mixture was quenched with saturated NaHCO₃ aqueous (100 mL)at 10° C. The DCM phase was separated and washed with saturatedNaHCO₃/Na₂S₂O₃ aqueous (1:1, 3×100 mL), brine (2×50 mL), dried overNa₂SO₄, filtered and concentrated under vacuum. The residue was purifiedby flash column (0˜30% of EtOAc in PE) to give 48.4 (1 g, 38.7%). ¹H NMR(400 MHz, CDCl₃) δ_(H) 2.49 (dd, J=8.8, 10.8 Hz, 1H), 2.22-2.13 (m, 1H),2.11 (s, 3H), 2.09-2.00 (m, 1H), 1.97-1.79 (m, 5H), 1.75-1.59 (m, 3H),1.51-1.29 (m, 9H), 1.28 (s, 4H), 1.25-0.99 (m, 3H), 0.96 (d, J=7.2 Hz,3H), 0.78 (s, 3H). LC-ELSD/MS purity: 99%, MS ESI calcd. forC₂₂H₃₆O₂[M−H₂O+H]⁺ 315.3, found C₂₂H₃₆O₂ [M−H₂O+H]⁺315.2.

Synthesis of 48.5

To a mixture of MePPh₃Br (2.24 g, 6.30 mmol) in THE (27 mL) was addedt-BuOK (706 mg, 6.30 mmol) at 20° C. under N₂. After stirring at 50° C.for 30 min, 48.4 (700 mg, 2.10 mmol) in THE (3 mL) was added in portionsbelow 50° C. After stirring at 50° C. for 16 h, the reaction mixture wasquenched with 10% NH₄Cl aqueous (20 mL) at 15° C. and extracted withEtOAc (3×20 mL). The combined organic phase was washed with brine (2×20mL), dried over anhydrous Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by flash column (0˜20% of ethyl acetatein PE) to give 48.5 (620 mg, 89.3%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 4.84(s, 1H), 4.71 (s, 1H), 2.16-1.95 (m, 3H), 1.91-1.77 (m, 4H), 1.76 (s,3H), 1.69-1.58 (m, 3H), 1.49-1.39 (m, 5H), 1.37-1.28 (m, 4H), 1.27 (s,4H), 1.24-0.99 (m, 6H), 0.95 (d, J=7.2 Hz, 3H), 0.91-0.82 (m, 2H), 0.72(s, 3H).

Synthesis of 48.6

To a solution of 48.5 (200 mg, 0.6050 mmol) in DCM (3 ml) was addedm-CPBA (194 mg, 0.9074 mmol). After stirring at 20° C. for 20 min,saturated aqueous NaHCO₃ (30 mL) and Na₂S₃O₃(30 mL) were added. Afterstirring for another 5 min, the aqueous phase was extracted with DCM(3×30 mL). The combined organic phase was washed with brine (20 mL),dried over anhydrous Na₂SO₄, filtered and concentrated to give 48.6 (240mg). ¹H NMR (400 MHz, CDCl₃) δ_(H) 2.91 (d, J=4.4 Hz, 1H), 2.54 (d,J=4.4 Hz, 1H), 1.76-2.16 (m, 10H), 1.51-1.73 (m, 11H), 1.39-1.49 (m,6H), 1.34-1.37 (m, 4H), 1.27 (s, 5H), 1.00-1.24 (m, 8H), 0.95 (s, 1H),0.94-0.96 (m, 1H), 0.88-0.93 (m, 5H), 0.85 (s, 3H).

Synthesis of 48 & 49

To a solution of 48.6 (340 mg, 0.9810 mmol) in DMF (5 mL) were added1H-pyrazole-4-carbonitrile (273 mg, 2.94 mmol) and Cs₂CO₃ (963 mg, 2.94mmol) at 25° C. After stirring at 120° C. for 16 h, the mixture wasadded water (20 mL) and extracted with EtOAc (120 mL). The combinedorganic solution was washed with brine (70 mL), dried over anhydrousNa₂SO₄, filtered, concentrated in vacuum. The residue was purified bycolumn (0%-55% of EtOAc in PE) to give a mixture of diastereomers, whichwas separated by SFC (column: DAICEL CHIRALPAK AS (250 mm*30 mm, 10 um);Mobile phase: A: CO₂ B: 0.1% NH₃H₂O ETOH; gradient: from 25% to 25% ofB, Flow Rate (ml/min): 70) to give 48 (158.2 mg, 93%) and 49 (73.8 mg,43%).

48: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.92 (s, 1H), 7.82 (s, 1H), 4.44-3.93(m, 2H), 2.54 (s, 1H), 2.25-2.07 (m, 2H), 2.00-1.92 (m, 1H), 1.90-1.77(m, 3H), 1.74-1.56 (m, 3H), 1.54-1.29 (m, 9H), 1.27 (s, 4H), 1.26-1.25(m, 1H), 1.25-1.09 (m, 4H), 1.06 (s, 4H), 1.00 (s, 3H), 0.96 (d, J=6.8Hz, 3H).LC-ELSD/MS purity: 99%, MS ESI calcd. for C₂₇H₄₁N₃O₂ [M−2H₂O+H]⁺404.3, found C₂₇H₄₁N₃O₂ [M−2H₂O+H]⁺ 404.3.

49: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.89 (s, 1H), 7.80 (s, 1H), 4.28-3.96(m, 2H), 2.27 (s, 1H), 2.22-1.96 (m, 3H), 1.91-1.78 (m, 3H), 1.75-1.56(m, 4H), 1.53-1.30 (m, 8H), 1.27 (s, 4H), 1.26-1.10 (m, 4H), 1.07 (s,4H), 1.03 (s, 3H), 0.97 (d, J=6.4 Hz, 3H)LC-ELSD/MS purity: 99%, MS ESIcalcd. for C₂₇H₄₁N₃O₂ [M−2H₂O+H]⁺ 404.3, found C₂₇H₄₁N₃O₂[M−2H₂O+H]⁺404.3.

EXAMPLE 50 & 51: Synthesis of1-((S)-2-hydroxy-2-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,3,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile(50) &1-((R)-2-hydroxy-2-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,3,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile(51)

Synthesis of 50.1

To a solution of 34.1 (50 g, 128 mmol) in THE (300 mL) was added LiHMDS(115 mL, 1 M in THF, 115 mL) at −70° C. under N₂. After stirring at −70°C. for 1 h, HMPA (27.4 g, 153 mmol) was added. After stirring at −70° C.for 30 minutes, MeI (109 g, 768 mmol) was added. After stirring at 25°C. for 1 h, the mixture was quenched with NH₄Cl (200 mL, sat.) andextracted with EtOAc (300 mL). The combined organic layer was separated,dried over Na₂SO₄, filtered and concentrated. The residue was purifiedby flash column (0-3% of EtOAc in PE) to give 50.1 (6 g, 11.6%). ¹H NMR(400 MHz, CDCl₃) δ_(H) 5.73 (s, 1H), 3.57 (t, J=8.4 Hz, 1H), 2.47-2.34(m, 2H), 2.29-2.19 (m, 1H), 2.17-2.09 (m, 1H), 1.99-1.74 (m, 5H),1.58-1.40 (m, 2H), 1.35-1.25 (m, 4H), 1.10 (d, J=7.2 Hz, 3H), 1.05-0.91(m, 4H), 0.88 (s, 9H), 0.76 (s, 3H), 0.01 (d, J=2.8 Hz, 6H).

Synthesis of 50.2

To a mixture of 50.1 (16 g, 2.48 mmol) in pyridine (200 mL) was addedPd/C (2 g, 10%). After hydrogenating under 15 psi of hydrogen at 25° C.for 24 h, the reaction mixture was filtered through a pad of Celite andwashed with pyridine (3×150 mL). The filtrate was concentrated andwashed with 1M HCl (200 mL). The aqueous phase was extracted with EtOAc(2×150 mL). The combined organic phase was washed with brine (20 mL),dried over anhydrous Na₂SO₄, filtered and concentrated to give 50.2 (16g). ¹H NMR (400 MHz, CDCl₃) δ_(H) 3.58 (t, J=8.8 Hz, 1H), 2.66-2.57 (m,1H), 2.38-2.30 (m, 1H), 2.22-2.14 (m, 2H), 2.09-2.04 (m, 1H), 1.94-1.84(m, 1H), 1.82-1.77 (m, 1H), 1.76-1.63 (m, 2H), 1.53-1.13 (m, 9H),1.13-0.99 (m, 4H), 0.97 (d, J=6.8 Hz, 3H), 0.88 (s, 9H), 0.74 (s, 3H),0.01 (d, J=2.8 Hz, 6H).

Synthesis of 50.3

To a solution of BHT (30 g, 136 mmol) in toluene (150 mL) under nitrogenat −70° C. in three-necked flask (1000 mL) was added trimethylaluminum(34 mL, 2 M in toluene, 68 mmol) dropwise. After stirring at −70° C. for1 h, to the MAD (56.7 g in toluene, 118 mmol) solution was added asolution of 50.2 (16 g, 39.5 mmol) in toluene (100 mL) and DCM (100 mL)dropwise at −70° C. under N₂. After stirring at −70° C. for 1 h, MeMgBr(39.3 mL, 3M, 118 mmol) was added dropwise at −70° C. After stirring for2 h, the reaction mixture was poured slowly into saturated aqueouscitric acid (500 mL) at 10° C. The aqueous phase was extracted with DCM(2×400 mL). The combined organic phase was washed with brine (300 mL),dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue waspurified by flash column (0-2% of EtOAc in PE) to give 50.3 (7.87 g,44.7%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 3.55 (t, J=8.0 Hz, 1H), 1.92-1.79(m, 3H), 1.77-1.71 (m, 2H), 1.68-1.63 (m, 1H), 1.62-1.58 (m, 1H),1.53-1.48 (m, 1H), 1.47-1.36 (m, 4H), 1.30-1.23 (m, 5H), 1.10 (s, 3H),1.07-0.95 (m, 6H), 0.87 (s, 9H), 0.86-0.84 (m, 3H), 0.69 (s, 3H), 0.00(d, J=2.4 Hz, 6H).

Synthesis of 50.4

To a solution of 50.3 (12.25 g, 30.1 mmol) in THE (150 mL) was addedTBAF (3.93 g, 120 mmol). After stirring at 80° C. for 3 h, the mixturewas poured into water (200 mL) and extracted with EtOAc (2×200 mL). Thecombined organic phase was washed with brine (200 mL), dried overanhydrous Na₂SO₄, filtered, and concentrated. The residue was purifiedby flash column (0˜15% of EtOAc in PE) to give 50.4 (8 g, 91.5%). ¹H NMR(400 MHz, CDCl₃) δ_(H) 3.64 (t, J=8.0 Hz, 1H), 2.10-2.02 (m, 1H),1.83-1.68 (m, 3H), 1.51-1.45 (m, 2H), 1.44-1.36 (m, 4H), 1.32-1.23 (m,7H), 1.10 (s, 3H), 1.08-1.02 (m, 5H), 0.86 (d, J=6.8 Hz, 5H), 0.74 (s,3H).

Synthesis of 50.5

To a solution of 50.4 (6.2 g, 20.2 mmol) in DCM (100 mL) was added DMP(17.1 g, 40.4 mmol) at 25° C. under N₂. After stirring at 25° C. for 2h, the mixture was quenched with NaHCO₃/NaS₂SO₃ (v:v=1:1) (200 mL) andextracted with DCM (2×100 mL). The combined organic phase was washedwith brine (100 mL), dried over anhydrous Na₂SO₄, filtered, andconcentrated. The residue was purified by flash column (0˜10%-20% ofEtOAc in PE) to give 50.5 (5.9 g, 95.9%). ¹H NMR (400 MHz, CDCl₃) δ_(H)2.44 (dd, J=8.4, 19.6 Hz, 1H), 2.13-2.03 (m, 1H), 1.97-1.89 (m, 1H),1.84-1.71 (m, 4H), 1.69-1.61 (m, 1H), 1.53-1.40 (m, 3H), 1.38-1.24 (m,7H), 1.23-1.15 (m, 2H), 1.11 (s, 3H), 0.90-0.83 (m, 9H).

Synthesis of 50.6

To a solution EtPPh₃Br (21.4 g, 57.9 mmol) in THE (50 mL) was addedt-BuOK (6.49 g, 57.9 mmol) at 25° C. under N₂. After stirring at 25° C.for 30 min, 50.5 (5.9 g, 19.3 mmol) in THE (50 mL) was added. Afterstirring at 45° C. for 16 h, the mixture was poured into NH₄Cl (100 mL)and extracted with EtOAc (2×150 mL). The combined organic phase waswashed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash column (0˜8% of EtOAc inPE) to give 50.6 (7 g). ¹H NMR (400 MHz, CDCl₃) δ_(H) 5.15-5.07 (m, 1H),2.41-2.31 (m, 1H), 2.28-2.13 (m, 2H), 1.84-1.80 (m, 2H), 1.78-1.68 (m,3H), 1.67-1.62 (m, 4H), 1.55-1.50 (m, 2H), 1.49-1.45 (m, 1H), 1.42 (s,1H), 1.40-1.29 (m, 3H), 1.26 (t, J=7.2 Hz, 3H), 1.21-1.14 (m, 2H), 1.10(s, 3H), 1.09-1.06 (m, 2H), 0.87-0.85 (m, 6H).

Synthesis of 50.7

To a solution of 50.6 (7 g, 22.1 mmol) in THE (100 mL) was added 9-BBNdimer (10.6 g, 44.2 mmol) under N₂. After stirring at 40° C. for 1 h,the mixture was cooled to room temperature, and sequentially treatedwith EtOH (12.6 mL, 221 mmol) and NaOH (44.2 mL, 5M, 221 mmol).H₂O₂(22.1 mL, 10M, 221 mmol) was then added very slowly, keeping theinner temperature below 15° C. After diluting with saturated aqueousNa₂S₂O₃ (150 mL), the mixture was stirred at 25° C. for 1 h. Thereaction was checked by potassium iodide-starch test paper to confirmexcess H₂O₂ was destroyed. The reaction mixture was filtered to give50.7 (12.3 g). ¹H NMR (400 MHz, CDCl₃) δ_(H) 3.75-3.65 (m, 1H),1.95-1.80 (m, 4H), 1.76-1.70 (m, 1H), 1.66-1.60 (m, 3H), 1.58-1.45 (m,4H), 1.43-1.32 (m, 3H), 1.30 (s, 2H), 1.24-1.21 (m, 4H), 1.16-1.11 (m,2H), 1.10 (s, 4H), 1.08-0.96 (m, 4H), 0.86 (d, J=6.8 Hz, 3H), 0.66 (s,3H).

Synthesis of 50.8

To a solution of 50.7 (12.3 g, 36.7 mmol) in DCM (200 mL) was added DMP(46.6 g, 110 mmol) in portions. After stirring at 25° C. for 3 h, themixture was poured into NaS₂SO₃/NaHCO₃ (v:v,1:1, 1000 mL) and extractedwith DCM (2×500 mL). The combined organic phase was washed with brine(200 mL), dried over anhydrous Na₂SO₄, filtered and concentrated to give50.8 (4.6 g, 37.7%). ¹H NMR (400 MHz, CDCl3) δ_(H) 2.53 (t, J=9.2 Hz,1H), 2.20-2.12 (m, 1H), 2.11 (s, 3H), 2.04-1.97 (m, 1H), 1.82 (d, J=6.4Hz, 2H), 1.76-1.68 (m, 2H), 1.67-1.52 (m, 6H), 1.44-1.37 (m, 3H),1.36-1.28 (m, 2H), 1.26-1.13 (m, 3H), 1.11 (s, 3H), 1.09-1.01 (m, 3H),0.87 (d, J=6.8 Hz, 3H), 0.61 (s, 3H).

Synthesis of 50.9

To a solution of MePPh₃Br (14.7 g, 41.4 mmol) in THE (30 mL) was addedt-BuOK (4.64 g, 41.4 mmol) at 25° C. under N₂. After stirring at 25° C.for 1 h, a solution of 50.8 (4.6 g, 13.8 mmol) in THE (20 mL) was added.After stirring at 40° C. for 2 h, the reaction was poured into water (20mL) and extracted with EtOAc (2×50 mL). The combined organic phase waswashed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash column (0-10% of EtOAcin PE) to give 50.9 (2.7 g, 39.9%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 4.84(s, 1H), 4.70 (s, 1H), 2.07-1.99 (m, 1H), 1.88-1.80 (m, 3H), 1.75 (s,4H), 1.73-1.48 (m, 8H), 1.47-1.13 (m, 8H), 1.11-1.09 (m, 3H), 1.07-0.98(m, 3H), 0.86 (d, J=6.8 Hz, 3H), 0.57 (s, 3H).

Synthesis of 50.10

To a solution of 50.9 (250 mg, 0.7563 mmol) in DCM (5 mL) was addedm-CPBA (260 mg, 1.51 mmol) at 25° C. After stirring at 25° C. for 1 h,the mixture was poured into water (20 mL) and extracted with DCM (2×20mL). The combined organic phase was washed with NaHCO₃/NaS₂SO₃ (1:1)(2×20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. Theresidue was purified by flash column (5%˜15% of EtOAc in PE) to give50.10 (290 mg). ¹H NMR (400 MHz, CDCl₃) δ_(H) 2.88 (d, J=4.8 Hz, 1H),2.55 (d, J=4.0 Hz, 1H), 2.49 (d, J=4.8 Hz, 0.5H), 2.32 (d, J=4.8 Hz,0.5H), 1.96-1.85 (m, 2H), 1.76-1.61 (m, 5H), 1.51-1.45 (m, 2H), 1.35 (s,3H), 1.31-1.24 (m, 4H), 1.23-1.13 (m, 3H), 1.10 (s, 4H), 1.08-1.01 (m,5H), 0.86 (d, J=6.8 Hz, 4H), 0.68 (s, 3H).

Synthesis of 50.11

To a solution of 50.10 (290 mg, 0.8368 mmol) in DMF (5 mL) were added1H-pyrazole-4-carbonitrile (155 mg, 1.67 mmol) and Cs₂CO₃ (817 mg, 2.51mmol) at 20° C. under N₂. After stirring at 130° C. for 16 h, themixture was poured into saturated H₂O (10 mL) and extracted with EtOAc(2×20 mL). The combined organic layer was washed with brine (20 mL),dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue waspurified by flash column (0˜20% of EtOAc in PE) to give 50.11 (250 mg,68.1%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.93 (s, 1H), 7.82 (s, 1H), 4.35(d, J=14.0 Hz, 1H), 4.08 (d, J=13.6 Hz, 1H), 2.51 (s, 1H), 2.04-1.98 (m,1H), 1.83-1.79 (m, 2H), 1.78-1.60 (m, 3H), 1.53-1.45 (m, 3H), 1.44-1.35(m, 4H), 1.33-1.24 (m, 3H), 1.22-1.13 (m, 3H), 1.10 (s, 4H), 1.09-1.03(m, 1H), 0.97 (s, 3H), 0.91 (s, 3H), 0.86 (d, J=6.4 Hz, 6H).

Separation of 50 & 51

50.11 (250 mg, 0.5686 mmol) was separated by SFC (Column: DAICELCHIRALPAK AD 250 mm×30 mm, 10 um; Condition: 0.1% NH₃H₂O ETOH; Gradient:from 45% to 45% of B; Flow rate: 80 mL/min; Column temperature: 40° C.)and then further purified by HPLC (Column: Phenomenex Gemini-NX 80 mm×40mm, 3 um; Condition: water(0.05% NH₃H₂O+10 mM NH₄HCO₃)-ACN); Gradient:from 57% to 87% of B in 8 min and hold 100% for 1.4 min; Flow rate: 30mL/min) to afford 51 (10.3 mg, 10.3%) and 50 (76.3 mg, 30.6%).

50: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.93 (s, 1H), 7.82 (s, 1H), 4.35 (d,J=13.2 Hz, 1H), 4.08 (d, J=14.0 Hz, 1H), 2.50 (s, 1H), 2.04-1.98 (m,1H), 1.84-1.79 (m, 2H), 1.77-1.60 (m, 6H), 1.52-1.35 (m, 5H), 1.31-1.17(m, 5H), 1.10 (s, 4H), 1.09-1.03 (m, 4H), 0.97 (s, 3H), 0.91 (s, 3H),0.86 (d, J=6.8 Hz, 3H). LC-ELSD/MS purity 99%, MS ESI calcd. forC₂₇H₃₈N₃ [M−2H₂O+H]⁺404.3, found 404.3. SFC 99% de.

51: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.89 (s, 1H), 7.80 (s, 1H), 4.19-4.13(m, 1H), 4.04-3.98 (m, 1H), 2.30 (s, 1H), 2.09-2.02 (m, 1H), 1.96-1.86(m, 1H), 1.84-1.79 (m, 2H), 1.75-1.61 (m, 5H), 1.53-1.45 (m, 3H),1.43-1.35 (m, 2H), 1.32-1.14 (m, 5H), 1.11-1.03 (m, 11H), 0.88-0.85 (m,6H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₇H₃₈N₃ [M−2H₂O+H]+404.3,found 404.3 SFC 100% de.

EXAMPLES 52 & 53: Synthesis of1-((S)-2-hydroxy-2-((2R,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,3,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile(52) &1-((R)-2-hydroxy-2-((2R,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,3,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile(53)

Synthesis of 52.1

To a solution of 52.0 (14.0 g, 51.0 mmol) in anhydrous THF (140 mL) wasadded a solution of LiAlH(OtBu)₃ (23.3 g, 91.8 mmol) in anhydrous THF(70 mL) dropwise at −40° C. over a period of 30 mins under N₂. Afterstirring at −40° C. for 2 h a suspension resulted, and the reactionmixture was poured into saturated NH₄Cl (150 mL) at 0° C., stirred for30 mins and extracted with EtOAc (3×150 mL). The combined organic phasewas washed with brine (300 mL), dried over anhydrous Na₂SO₄, filteredand concentrated to give 52.1 (13.92 g). ¹H NMR (400 MHz, CDCl₃) δ_(H)0.87 (s, 3H) 1.00-1.33 (m, 8H) 1.33-1.49 (m, 4H) 1.52-1.58 (m, 3H)1.66-1.72 (m, 2H) 1.75-1.84 (m, 3H) 1.89-1.98 (m, 2H) 2.05-2.14 (m, 1H)2.39-2.49 (m, 1H) 3.63 (br s, 1H).

Synthesis of 52.2

To a solution of 52.1 (13.0 g, 47.0 mmol) in DCM (130 mL) was added1-methyl-1H-imidazole (7.70 g, 94.0 mmol) and TEA (9.49 g, 94.0 mmol) at25° C., followed by TsCl (17.9 g, 94.0 mmol). After stirring at 25° C.for 2 h, the residue was poured into ice-water (250 mL) and stirred for20 mins. The aqueous phase was extracted with EtOAc (2×200 mL). Thecombined organic phase was washed with brine (2×250 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under vacuum to give 52.2(16.0 g). ¹H NMR (400 MHz, CDCl₃) δ_(H) 0.84 (s, 3H) 0.93-0.93 (m, 1H)0.95-1.16 (m, 3H) 1.17-1.36 (m, 5H) 1.38-1.58 (m, 4H) 1.76-2.00 (m, 4H)2.02-2.27 (m, 3H) 2.36-2.37 (m, 1H) 2.39-2.43 (m, 1H) 2.44 (s, 3H)2.45-2.63 (m, 1H) 4.40-4.55 (m, 1H) 7.32 (d, J=8.13 Hz, 2H) 7.74-7.84(m, 2H).

Synthesis of 52.3 & 52.3A

To 52.2 (16.0 g, 37.1 mmol) was added collidine (150 mL, 37.1 mmol) at25° C. under N₂. After stirring at 140° C. for 16 h a solution resulted.The mixture was poured into water (500 mL), extracted with EtOAc (3×400mL). The combined organic phase was washed with water (3×100 mL), brine(200 mL), dried over anhydrous Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by flash column (0-20% of EtOAc in PE)to give a mixture of 52.3 and 52.3A (8.6 g). ¹H NMR (400 MHz, CDCl₃)δ_(H) 0.87 (s, 1H) 0.91 (s, 1H) 0.94-1.10 (m, 2H) 1.10-1.33 (m, 6H) 1.53(br dd, J=6.02, 2.76 Hz, 7H) 1.67-1.83 (m, 3H) 1.83-1.97 (m, 3H)2.28-2.72 (m, 3H) 5.31-5.55 (m, 1H) 5.60 (br s, 1H).

Synthesis of 52.4 & 52.4A

To a mixed solution of 52.3 and 52.3A (7.5 g, 29.0 mmol) in DCM (90 mL)was added m-CPBA (8.8 g, 43.5 mmol) at 0° C. under N₂. After stirring at25° C. for 2 h, the mixture was quenched with saturated NaHCO₃ (100 mL)and the mixture was extracted with DCM (2×150 mL). The organic layer waswashed with Na₂S₂O₃ (2×100 mL, sat.), brine (2×100 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue waspurified by flash column (0˜20% of EtOAc in PE) to give a mixture of52.4 and 52.4A (7 g). ¹H NMR (400 MHz, CDCl₃) δ_(H) 3.34-2.78 (m, 2H),2.54-2.33 (m, 1H), 2.20-2.02 (m, 2H), 1.96-1.49 (m, 11H), 1.39-0.97 (m,7H), 0.91-0.81 (m, 3H)

Synthesis of 52.5 & 52.5A

To a suspension of Ph₃PEtBr (24.2 g, 65.3 mmol) in anhydrous THE (100mL) was added t-BuOK (7.32 g, 65.3 mmol) at 15° C. under N₂ and themixture was stirred at 45° C. for 30 min. A mixture of 52.4 and 52.4A(6.0 g, 21.8 mmol) in anhydrous THE (15 mL) was then added dropwise.After stirring for 16 h the mixture was cooled and poured into ice-water(50 mL) and stirred for 10 min. The aqueous phase was extracted withEtOAc (2×50 mL) and the combined organic phase was washed with brine(2×50 mL), filtered, concentrated and purified by flash column (0˜10% ofEtOAc in PE) to give a mixture of 52.5 and 52.5A (5.5 g, 88%).

Synthesis of 52.6

To a suspension of CuI (1.80 g, 9.48 mmol) in THE (10 mL) was added MeLi(7.75 mL, 1.6 M, 12.4 mmol) at 0° C. After stirring at 0° C. for 1 h, amixture of 52.5 and 52.5A (0.3 g, 1.04 mmol) in THE (10 mL) was added at0° C. After stirring at 15° C. for 16 h the mixture was poured intowater (50 mL) and the aqueous phase was extracted with EtOAc (2×50 mL).The combined organic phase was washed with brine (50 mL), dried overanhydrous Na₂SO₄, filtered, concentrated and purified by flash column(0˜15% of EtOAc in PE) to give 52.6 (100 mg, 31.8%). ¹H NMR (400 MHz,CDCl₃) δ_(H) 5.12 (q, J=7.0 Hz, 1H), 3.55 (br s, 1H), 2.48-2.10 (m, 4H),1.98-1.68 (m, 4H), 1.68-1.65 (m, 4H), 1.55-1.11 (m, 13H), 1.06-0.97 (m,4H), 0.89 (s, 3H).

Synthesis of 52.7

To a solution of 52.6 (100 mg, 0.3305 mmol) in THE (10 mL) was added9-BBN dimer (159 mg, 0.661 mmol) under N₂. The reaction mixture wasstirred at 50° C. under N₂ for 2 h to give a colorless mixture. Themixture was cooled to 0° C., where ethanol (0.288 mL, 4.95 mmol) andNaOH (0.99 mL, 5 M, 4.95 mmol) were added, resulting in the mixtureturning clear. H₂O₂(560 mg, 30%, 4.95 mmol) was added dropwise at 15° C.After stirring at 50° C. for 2 h saturated aqueous Na₂S₂O₃ (50 mL) wasadded and the mixture was stirred at 0° C. for another 1 h. The reactionwas checked by potassium iodide-starch test paper to confirm excess H₂O₂was destroyed (did not changed to blue). The aqueous phase was extractedwith EtOAc (3×40 mL) and the combined organic phase was washed withbrine (2×50 mL), dried over anhydrous Na₂SO₄, filtered and concentratedto give 52.7 (800 mg).

Synthesis of 52.8

To a solution of 52.7 (900 mg, 2.80 mmol) in DCM (40 mL) was added DMP(4.74 g, 12.4 mmol) under N₂. After stirring at 15° C. under N₂ for 2 ha colorless mixture resulted, and saturated aqueous NaHCO₃ (50 mL) andsaturated aqueous Na₂S₂O₃ (50 mL) were added. The aqueous phase wasextracted with DCM (3×40 mL). The combined organic phase was washed withbrine (2×50 mL), dried over anhydrous Na₂SO₄, filtered, concentrated andpurified by flash column (0˜20% of EtOAc in PE) to give 52.8 (550 mg,62%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 2.62-2.31 (m, 4H), 2.12-1.95 (m,7H), 1.90-1.56 (m, 3H), 1.53-1.39 (m, 2H), 1.33-1.09 (m, 6H), 1.05 (d,J=6.8 Hz, 3H), 1.03-0.85 (m, 4H), 0.66 (s, 3H)

Synthesis of 52.9

To a solution of BHT (2.26 g, 10.3 mmol) in toluene (10 mL) undernitrogen at 0° C. was added AlMe₃ (2 M in toluene, 2.57 mL, 5.15 mmol)dropwise. The mixture was stirred at 20° C. for 1 h to give the MADsolution. To the MAD solution (4.71 mmol in 10 mL toluene) was added asolution of 52.8 (500 mg, 1.57 mmol) in anhydrous DCM (5 mL) dropwise at−70° C. After stirring at −70° C. for 1 h under N₂, MeMgBr (4.16 mL,12.5 mmol, 3 M in ethyl ether) was added drop wise at −70° C. Theresulting solution was stirred at −70° C. for 3 h. The reaction mixturewas poured into citric acid (30 mL, 20% aq.) at below 10° C. andextracted with EtOAc (2×30 mL). The combined organic layer was driedover Na₂SO₄, filtered, concentrated and purified by silica gelchromatography (0-30% of EtOAc in PE) to give 52.9 (300 mg, 57.4%). ¹HNMR (400 MHz, CDCl₃) δ_(H) 2.54 (br t, J=8.9 Hz, 1H), 2.23-2.13 (m, 1H),2.12 (s, 3H), 2.05-1.94 (m, 1H), 1.89-1.56 (m, 12H), 1.52-1.36 (m, 3H),1.28 (s, 3H), 1.25-1.09 (m, 6H), 1.08-0.94 (m, 5H), 0.63 (s, 3H).

Synthesis of 52.10

To a solution of MePPh₃Br (1.61 g, 4.51 mmol) in THE (40 mL) was addedt-BuOK (0.506 g, 4.51 mmol) at 15° C. under N₂. After stirring at 15° C.for 1 h, 52.9 (0.3 g, 0.9021 mmol) in THF (10 mL) was added. Afterstirring at 40° C. for 2 h, the mixture was poured into water (20 mL)and the aqueous phase was extracted with EtOAc (2×50 mL). The combinedorganic phase was washed with brine (20 mL), dried over anhydrousNa₂SO₄, filtered, concentrated and purified by flash column (0˜10% ofEtOAc in PE) to give 52.10 (180 mg, 60.4%). ¹H NMR (400 MHz, CDCl₃)δ_(H) 4.85 (s, 1H), 4.71 (s, 1H), 2.10-1.99 (m, 1H), 1.87-1.78 (m, 4H),1.76 (s, 3H), 1.73-1.57 (m, 7H), 1.49-1.38 (m, 2H), 1.28 (s, 3H),1.24-1.07 (m, 7H), 1.02 (d, J=7.0 Hz, 3H), 0.99-0.80 (m, 3H), 0.58 (s,3H).

Synthesis of 52.11

To a solution of 52.10 (90 mg, 0.2722 mmol) in DCM (10 mL) was addedm-CPBA (110 mg, 0.54 mmol, 85%) at 0° C. under N₂. After stirring at 15°C. for 2 h, the mixture was quenched with saturated NaHCO₃ (10 mL). Themixture was extracted with DCM (2×10 mL), the organic layer was washedwith Na₂S₂O₃ (2×10 mL, sat.), brine (2×10 mL), dried over anhydrousNa₂SO₄, filtered and concentrated to give 52.11 (100 mg).

Synthesis of 52 & 53

To a solution of 52.11 (100 mg, 0.2885 mmol) in DMF (5 mL) was added1H-pyrazole-4-carbonitrile (53.7 mg, 0.577 mmol) and Cs₂CO₃ (187 mg,0.577 mmol) at 20° C. under N₂. After stirring at 130° C. for 16 h, themixture was poured into H₂O (10 mL) and extracted with EtOAc (2×20 mL).The combined organic layer was washed with brine (20 mL), dried overanhydrous Na₂SO₄, filtered, concentrated and purified by SFC (ColumnDAICEL CHIRALPAK AS(250 mm*30 mm, 10 um) Condition 0.1% NH₃H₂O ETOHBegin B 20 End B 20 Gradient Time(min) 100% B Hold Time(min)FlowRate(ml/min) 60 Injections 170) to afford 52 (19.1 mg, 15.1%) and 53(14.7 mg, 11.6%).

52: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.93 (s, 1H), 7.82 (s, 1H), 4.36 (d,J=13.8 Hz, 1H), 4.09 (d, J=13.8 Hz, 1H), 2.51 (s, 1H), 2.01 (br d,J=11.3 Hz, 1H), 1.87-1.56 (m, 11H), 1.42 (br t, J=9.7 Hz, 5H), 1.28 (s,3H), 1.25-1.04 (m, 7H), 1.00 (br d, J=7.0 Hz, 3H), 0.98 (s, 3H), 0.93(s, 3H). LC-ELSD/MS purity 99%, MS ESI calcd. For C₂₇H₃₈N₃[M−2H₂O+H]⁺404.3, found 404.3. 53: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.82 (s, 1H), 7.73(s, 1H), 4.13-4.03 (m, 1H), 3.99-3.87 (m, 1H), 2.20 (s, 1H), 2.02-1.93(m, 1H), 1.80-1.53 (m, 9H), 1.44-1.25 (m, 9H), 1.20 (s, 3H), 1.15 (br s,4H), 1.02 (s, 3H), 0.93 (br d, J=7.3 Hz, 3H), 0.81 (s, 3H). LC-ELSD/MSpurity 99%, MS ESI calcd. For C₂₇H₃₈N₃ [M−2H₂O+H]⁺ 404.3, found 404.3.

EXAMPLES 54 & 55: Synthesis of1-((S)-2-((3R,5R,8R,9S,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methoxypropyl)-1H-pyrazole-4-carbonitrile(54) &1-((R)-2-((3R,5R,8R,9S,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methoxypropyl)-1H-pyrazole-4-carbonitrile(55)

Synthesis of 54.1

To a mixture of MePPh₃Br (10.4 g, 28.8 mmol) in THF (20 mL) was addedt-BuOK (3.7 g, 33.0 mmol) at 25° C. under N₂. The resulting mixture wasstirred at 45° C. for 30 min. 54.0 (8.0 g, 22.0 mmol) was added inportions below 45° C. After stirring at 55° C. for 3 h a suspensionresulted. The reaction mixture was quenched with 10% NH₄Cl aqueous (40mL) at 25° C. The aqueous layer was extracted with EtOAc (2×40 mL) andthe combined organic phase was separated, dried over Na₂SO₄, filtered,concentrated and purified by flash column (15˜35% of EtOAc in PE) togive 54.1 (3.1 g, 39%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 4.82-4.89 (m, 1H),4.50-4.73 (m, 1H), 3.36-3.42 (m, 4H), 2.56-2.61 (m, 1H), 1.77-2.03 (m,4H), 1.74 (s, 3H), 1.63-1.72 (m, 3H), 1.31-1.60 (m, 9H), 1.09-1.29 (m,7H), 0.91-0.95 (m, 3H), 0.78-0.89 (m, 1 H), 0.54 (s, 2H).

Synthesis of 54.2

To a solution of 54.1 (710 mg, 1.96 mmol), 2,6-dimethylpyridine (1.04 g,9.79 mmol) in DCM (7 mL) was added drop-wise tertbutyldimethylsilyltrifluoromethanesulfonate (2.07 g, 7.84 mmol) at 0° C. After stirring at25° C. for 36 h the reaction mixture was quenched with water (15 mL) andextracted with DCM (2×15 mL). The combined organic phase washed withbrine (15 mL), dried over Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by flash column (0˜5% of EtOAc in PE)to afford 54.2 (290 mg, 31%). ¹H NMR (400 MHz, CDCl₃), SH 4.85 (s, 1H),4.70 (s, 1H), 3.38-3.42 (m, 1H), 3.35 (s, 3H), 3.28-3.31 (m, 1H),1.65-1.85 (m, 12H), 1.31-1.47 (m, 10H), 1.09-1.28 (m, 9H), 0.92 (s, 3H),0.86-0.87 (m, 9H), 0.55 (s, 3H), 0.07-0.10 (m, 7H),

Synthesis of 54.3

To a solution of 54.2 (700 mg, 1.47 mmol) in DCM (10 mL) was addedm-CPBA (596 mg, 85%, 2.94 mmol). After stirring at 15° C. for 0.5 h acolorless solution resulted. The mixture was quenched with saturated aq.NaHCO₃ (100 mL). The DCM phase was separated and washed with saturatedNaHCO₃/Na₂S₂O₃ aqueous (1:1, 3×100 mL), brine (100 mL), dried overNa₂SO₄, filtered and concentrated under vacuum to give 54.3 (800 mg). ¹HNMR (400 MHz, CDCl₃), SH 3.42-3.28 (m, 5H), 2.88-2.87 (m, 0.6H),2.56-2.49 (m, 1H), 2.32-2.31 (m, 0.4H), 2.06-1.51 (m, 4H), 1.49-1.31 (m,10H), 1.26-0.91 (m, 12H), 0.86-0.66 (m, 15H), 0.08-0.07 (m, 6 H).

Synthesis of 54.4 & 55.1

To a solution of 54.3 (800 mg, 1.62 mmol) in DMF (20 mL), was added1H-pyrazole-4-carbonitrile (451 mg, 4.86 mmol) and Cs₂CO₃ (1.58 g, 4.86mmol). After stirring at 130° C. for 16 h the reaction mixture wasdiluted with water (100 mL) and extracted with EtOAc (3×100 mL). Thecombined organic layer was washed with 5% LiCl (3×100 mL) andconcentrated. The residue was purified by flash column (0˜ 12% of EtOAcin PE) to give 54.4 (340 mg) and 55.1 (380 mg).

54.4: ¹H NMR (400 MHz, CDCl₃), SH 7.92 (s, 1H), 7.81 (s, 1H), 4.37-4.34(m, 1H), 4.11-4.07 (m, 1H), 3.41-3.27 (m, 5H), 2.49 (s, 1H), 2.03-2.01(m, 1H), 1.85-1.62 (m, 7H), 1.56-1.26 (m, 8H), 1.23-0.94 (m, 13H),0.91-0.86 (m, 8H), 0.85-0.82 (m, 4H), 0.08-0.07 (m, 6H).

55.1: ¹H NMR (400 MHz, CDCl₃), SH 7.86-7.81 (m, 1H), 7.74-7.72 (m, 1H),4.11-3.91 (m, 2H), 3.34-3.20 (m, 5H), 2.02-1.56 (m, 8H), 1.44-1.07 (m,13H), 1.06-0.78 (m, 15H), 0.77-0.69 (m, 6H), 0.01-0.00 (m, 6H).

Synthesis of 54.5

To a solution of 54.4 (310 mg, 0.530 mmol) in THE (10 mL) was added NaH(211 mg, 5.30 mmol, 60%) at 0° C. under N₂ in 100 mL three-neck flask.After stirring at 25° C. for 0.5 h, MeI (752 mg, 5.30 mmol) was addedinto the reaction mixture. After stirring at 25° C. for 16 h, thereaction mixture was quenched by ammonia (1 mL) and poured into water(50 mL). The aqueous phase was extracted with EtOAc (2×50 mL). Thecombined organic layer was washed with brine (2×50 mL), dried overanhydrous Na₂SO₄, filtered and concentrated to give 54.5 (470 mg). ¹HNMR (400 MHz, CDCl₃), SH 7.91 (s, 1H), 7.75 (s, 1H), 4.30-4.18 (m, 2H),3.41-3.27 (m, 5H), 3.17 (s, 3H), 1.98-1.59 (m, 10H), 1.41-1.29 (m, 7H),1.25-1.17 (m, 5H), 1.14-1.05 (m, 4H), 0.91-0.83 (m, 15H), 0.07-0.06 (m,6H).

Synthesis of 54

To a solution of 54.5 (470 mg, 0.786 mmol) in THE (20 mL) was added TBAF(1.63 g, 6.28 mmol). After stirring at 80° C. for 16 h a solutionresulted, and the reaction mixture was quenched with saturated aq. NH₄Clsolution (30 mL) and extracted with EtOAc (2×50 mL). The combinedorganic layer was washed with saturated brine (100 mL), dried overanhydrous Na₂SO₄, filtered and concentrated to give a residue, which waspurified by flash column (0˜50% of EtOAc in PE) to give 54 (150 mg),which was further purified by SFC (Column DAICEL CHIRALCEL OD-H (250mm*30 mm, 5 um); Condition 0.1% NH₃H₂O EtOH; Begin B 50%; End B 50%;Flow Rate (ml/min) 80; Injections 45) to provide 54 (95.9 mg, 64%). ¹HNMR (400 MHz, CDCl₃), SH 7.90 (s, 1H), 7.75 (s, 1H), 4.28-4.17 (m, 2H),3.41-3.34 (m, 5H), 3.17 (s, 3H), 2.56 (s, 1H), 1.98-1.58 (m, 6H),1.50-1.10 (m, 13H), 1.09-0.93 (m, 10H), 0.82 (s, 3H). LC-ELSD/MS purity99%, MS ESI calcd. For C₂₇H₃₇N₃ [M−2MeOH-H₂O+H]⁺402.3 found 402.3.

Synthesis of 55.2

To a solution of 55.1 (310 mg, 0.530 mmol) in THE (10 mL) was added NaH(211 mg, 5.30 mmol, 60%) at 0° C. under N₂ in 100 mL three-neck flask.After stirring at 25° C. for 0.5 h, MeI (752 mg, 5.30 mmol) was addedinto the reaction mixture. After stirring at 25° C. for 16 h, thereaction mixture was quenched by ammonia (1 mL) and poured into water(50 mL). The aqueous phase was extracted with EtOAc (2×50 mL) and thecombined organic phase was washed with brine (2×50 mL), dried overanhydrous Na₂SO₄, filtered and concentrated to give 55.2 (500 mg). ¹HNMR (400 MHz, CDCl₃), SH 7.90 (s, 1H), 7.75 (s, 1H), 4.35-4.24 (m, 2H),3.41-3.27 (m, 5H), 3.15 (s, 3H), 2.07-1.60 (m, 7H), 1.39-1.25 (m, 8H),1.24-1.07 (m, 7H), 1.05-0.90 (m, 4H), 0.89-0.83 (m, 7H), 0.82-0.78 (m,8H), 0.08-0.07 (m, 6H).

Synthesis of 55

To a solution of 55.2 (500 mg, 0.836 mmol) in THE (20 mL) was added TBAF(1.74 g, 6.68 mmol). After stirring at 80° C. for 16 h a solutionresulted, and the reaction mixture was quenched with saturated aq. NH₄Clsolution (30 mL) and extracted with EtOAc (2×50 mL). The combinedorganic phase was washed with saturated brine (100 mL), dried overanhydrous Na₂SO₄, filtered and concentrated to give a residue, which waspurified by flash column (0˜50% of EtOAc in PE) to give 55 (250 mg),which was further purified by SFC (Column DAICEL CHIRALCEL OD-H (250mm*30 mm, 5 um); Condition 0.1% NH₃H₂O ETOH; Begin B 50%; End B 50%;Flow Rate (ml/min) 80; Injections 60), to provide 55 (71.2 mg, 28.5%).¹H NMR (400 MHz, CDCl₃), SH 7.90 (s, 1H), 7.75 (s, 1H), 4.27-4.20 (m,2H), 3.42-3.35 (m, 5H), 2.58 (s, 3H), 2.05-1.57 (m, 7H), 1.51-1.06 (m,15H), 1.00-0.93 (m, 8H), 0.79 (s, 3H). LC-ELSD/MS purity 99%, MS ESIcalcd. For C₂₇H₃₇N₃[M−2MeOH-H₂O+H]⁺402.3 found 402.3.

EXAMPLE 56: Synthesis of1-(2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylpropyl)-1H-pyrazole-4-carbonitrile(56)

Synthesis of 56.1

To a solution of EtPh₃PBr (41.5 g, 112 mmol) in THE (110 mL) was addedt-BuOK (12.5 g, 112 mmol) at 25° C. The mixture was stirred at 50° C.for 1 h where a solution of 40.0 (12.0 g, 37.4 mmol) in THE (50 mL) wasadded into the reaction mixture below 50° C. After stirring at 40° C.for 16 h the mixture was added into saturated NH₄Cl (100 mL). Theaqueous layer was extracted with EtOAc (3×150 mL) and the combinedorganic layer was washed with saturated brine (100 mL), dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was purified byflash column (0˜30% of EtOAc in PE) to give 56.1 (14.0 g). ¹H NMR (400MHz, CDCl₃) δ_(H) 5.15-5.05 (m, 1H), 3.42-3.37 (m, 5H), 2.41-2.30 (m,1H), 2.27-2.11 (m, 2H), 1.88-1.80 (m, 1H), 1.74-1.68 (m, 1H), 1.66-1.63(m, 3H), 1.63-1.59 (m, 2H), 1.56-1.53 (m, 1H), 1.52-1.45 (m, 2H),1.44-1.35 (m, 5H), 1.35-1.18 (m, 5H), 1.17-1.02 (m, 4H), 0.87 (s, 3H)

Synthesis of 56.2

To a mixture of 56.1 (14.0 g, 42.1 mmol) in DMF (150 mL) was added NaH(6.71 g, 168 mmol, 60% in mineral oil) at 0° C. The mixture was stirredat 25° C. for 1 h and BnBr (28.7 g, 168 mmol) was added. After stirringat 60° C. for 20 h triethylamine (50 mL) was added and the mixture wasstirred at 60° C. for another 30 min. The mixture was added into NH₄Cl(100 mL) and the aqueous phase was extracted with EtOAc (3×100 mL). Thecombined organic phase was washed with saturated brine (2×100 mL), driedover anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by flash column (0-20% of EtOAc in PE) to give 56.2 (18.8 g).¹H NMR (400 MHz, CDCl₃) δ_(H) 7.37-7.37 (m, 1H), 7.36 (s, 1H), 7.33 (s,1H), 7.31 (s, 1H), 7.29 (s, 1H), 5.17-5.05 (m, 1H), 4.57 (s, 2H), 3.58(d, J=4.0 Hz, 2H), 3.38 (s, 3H), 2.42-2.31 (m, 1H), 2.28-2.11 (m, 2H),1.94-1.83 (m, 1H), 1.79-1.70 (m, 2H), 1.69-1.63 (m, 4H), 1.62-1.57 (m,2H), 1.54-1.51 (m, 1H), 1.50-1.37 (m, 4H), 1.37-1.31 (m, 1H), 1.30-1.21(m, 3H), 1.18-0.99 (m, 4H), 0.88 (s, 3H).

Synthesis of 56.3

To a solution of 56.2 (18.8 g, 44.4 mmol) in THE (200 mL) was added9-BBN dimer (32.4 g, 133 mmol) at 25° C. The mixture was stirred at 40°C. for 1 h. To the resulting mixture was added ethanol (10.2 g, 222mmol) at 0° C. Then aqueous NaOH (44.4 mL, 5M) was added at 0° C.followed by H₂O₂(22.2 mL, 10M, 222 mmol) dropwise. After the addition,the mixture was stirred at 80° C. for 1 h. Sat. Na₂S₂O₃ (100 mL) wasadded and the mixture stirred for 30 mins. The aqueous layer wasextracted with EtOAc (200 mL), washed with saturated brine (2×100 mL),dried over anhydrous Na₂SO₄ and the combined organic phase wasconcentrated under vacuum to give 56.3 (13.0 g).

Synthesis of 56.4

To a solution of 56.3 (3.0 g, 6.8 mmol) in DCM (30 mL) was added silicagel (6.6 g) and PCC (4.38 g, 20.4 mmol) at 25° C. After stirring at 25°C. for 25 min the suspension was filtered, and the filter cake waswashed with DCM (2×50 mL). The combined filtrate was concentrated, andthe residue was purified by silica gel chromatography (0-20% of EtOAc inPE) to give 56.4 (2.6 g, 87.2%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.40-7.29(m, 4H), 7.25-7.21 (m, 1H), 4.58 (s, 2H), 3.59 (d, J=3.6 Hz, 2H), 3.38(s, 3H), 2.55 (t, J=8.4 Hz, 1H), 2.19-2.13 (m, 1H), 2.11 (s, 3H),2.03-1.96 (m, 1H), 1.92-1.79 (m, 3H), 1.77-1.59 (m, 5H), 1.54-1.32 (m,7H), 1.31-1.03 (m, 6H), 0.61 (s, 3H).

Synthesis of 56.5

To a stirred solution of t-BuOK (1.01 g, 9.08 mmol) in t-BuOH (10 mL)was added a solution of 56.4 (1.0 g, 2.27 mmol) in DME (10 mL) and asolution of Tosmic (886 mg, 4.54 mmol) in DME (10 mL) under N₂. Afterstirring at 25° C. for 72 h the mixture was quenched by aq.NH₄Cl (40 mL,sat.) and extracted with EtOAc (2×50 mL). The combined organic layer wasdried over Na₂SO₄, filtered, concentrated and purified by flash columnchromatography on silica gel (0-15% EtOAc in PE) to give 56.5 (1.0 g,98%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.29-7.39 (m, 4H) 7.20-7.25 (m, 1H)4.58 (s, 2H) 3.53-3.64 (m, 2H) 3.38 (s, 3H) 2.25-2.70 (m, 2H) 1.60-2.08(m, 10H) 1.26-1.45 (m, 9H) 0.89-1.22 (m, 7H) 0.73 (d, J=2.00 Hz, 3H)

Synthesis of 56.6

To a solution of DIPEA (3.12 mL, 22.2 mmol) in THE (50 mL) under N₂ wasadded n-BuLi (10.6 mL, 2.5 M in hexane, 26.6 mmol) at −70° C. Themixture was warmed to 0° C. and stirred for 0.5 h under N₂. The freshlyprepared LDA (2.37 g, 22.2 mmol) was added to a stirred solution of 56.5(1.0 g, 2.22 mmol) under N₂ in THF (50 mL) at −70° C. The mixture wasstirred at −70° C. for 1 h where methyl iodide (3.15 g, 22.2 mmol) wasadded under N₂ and the mixture was then warmed to 20° C. for 16 h. Water(50 mL) was added and the aqueous phase was extracted with EtOAc (3×50mL). The combined organic layers were washed with brine (50 mL), driedover anhydrous Na₂SO₄, filtered, concentrated and purified by flashcolumn (0˜2% of EtOAc in PE) to afford 56.6 (900 mg). ¹H NMR (400 MHz,CDCl₃) δ_(H) 7.35-7.20 (m, 4H), 7.20-7.05 (m, 1H), 4.55-4.45 (m, 2H),3.55-3.45 (m, 2H), 3.30 (s, 3H), 2.00-1.90 (m, 1H), 1.90-1.65 (m, 9H),1.65-1.50 (m, 3H), 1.50-1.40 (m, 2H), 1.36-1.27 (m, 13H), 1.27-1.15 (m,6H), 1.15-0.95 (m, 2H), 0.87-0.80 (m, 4H), 0.80-0.75 (m, 3H).

Synthesis of 56.7

To a solution of 56.6 (900 mg, 1.88 mmol) in DCM (10 mL) a solution ofDIBAL-H (9.40 mL, 9.40 mmol, 1 M in toluene) was added slowly at −70° C.After stirring for 30 mins at −70° C., HCl (4 ml, 0.468 M, 1.88 mmol)was added. After stirring at 25° C. for another 10 mins the mixture wascarefully poured into H₂O (30 mL), extracted with EtOAc (2×30 mL), driedover Na₂SO₄, filtered and concentrated to give 56.7 (800 mg). ¹H NMR(400 MHz, CDCl₃) δ_(H) 9.70 (s, 1H), 7.45-7.30 (m, 4H), 7.30-7.20 (m,1H), 4.65-4.50 (m, 2H), 3.65-3.50 (m, 2H), 3.40 (s, 3H), 2.00-1.85 (m,2H), 1.85-1.60 (m, 10H), 1.60-1.55 (m, 2H), 1.56-1.35 (m, 5H), 1.34-1.21(m, 14H), 1.20-1.15 (m, 3H), 1.14-0.95 (m, 8H), 0.90-0.88 (m, 8H),0.87-0.75 (m, 6H), 0.70 (s, 2H).

Synthesis of 56.8

To a suspension of 56.7 (800 mg, 1.71 mmol) in anhydrous MeOH (20 mL)was added NaBH₄ (323 mg, 8.55 mmol) slowly at 0° C. After stirring at20° C. for 30 min a colorless mixture resulted. The mixture was pouredinto H₂O (20 mL) slowly and extracted with EtOAc (2×20 mL). The combinedorganic layers were washed with brine (10 mL), dried over Na₂SO₄,filtered, concentrated and purified by flash column (0˜7% of EtOAc inPE) to give 56.8 (500 mg, 62%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.40-7.30(m, 4H), 7.25-7.20 (m, 1H), 4.55-4.50 (m, 2H), 3.70-3.55 (m, 2H),3.45-3.25 (m, 5H), 2.05-1.95 (m, 1H), 1.90-1.75 (m, 4H), 1.70-1.52 (m,7H), 1.50-1.35 (m, 5H), 1.32-1.20 (m, 6H), 1.20-0.95 (m, 5H), 0.99 (s,3H), 0.90 (s, 3H).

Synthesis of 56.9

To a solution of 56.8 (500 mg, 1.06 mmol) in MeOH (20 mL) was added Pd/C(50 mg) under N₂. After hydrogenation at 50° C. under 50 psi for 16 h,the reaction mixture was filtered through a pad of Celite and washedwith EtOAc (3×50 mL). The filtrate was concentrated to give 56.9 (270mg). ¹H NMR (400 MHz, CDCl₃) δ_(H) 3.50-3.35 (m, 7H), 2.58 (s, 1H),2.10-1.95 (m, 1H), 1.90-1.75 (m, 4H), 1.70-1.55 (m, 3H), 1.50-1.35 (m,8H), 1.30-1.20 (m, 4H), 1.15-1.10 (m, 4H), 1.01 (s, 3H), 0.92 (s, 3H),0.78 (s, 3H).

Synthesis of 56.10

To a solution of 56.9 (50 mg, 0.132 mmol) in DCM (10 mL) was added1-methyl-1H-imidazol (21.6 mg, 0.264 mmol), TEA (0.0365 ml, 0.264 mmol)and TsCl (25.1 mg, 0.132 mmol). After stirring at 20° C. for 1 h, themixture was washed with water (5 mL) and the aqueous layer was extractedwith DCM (3×20 mL). The combined organic layer was washed with brine (50mL), dried over anhydrous Na₂SO₄, filtered and concentrated to give56.10 (50 mg).

Synthesis of 56

To a solution of 56.10 (200 mg, 0.375 mmol) in DMF (20 mL) was addedCs₂CO₃ (244 mg, 0.750 mmol) and 4-cyano-pyrazole (104 mg, 1.12 mmol) at25° C. After stirring at 120° C. for 12 h, the mixture was washed withwater (10 mL) and the aqueous phase was extracted with EtOAc (2×10 mL).The combined organic phase was washed with brine (2×10 mL), dried overanhydrous Na₂SO₄, filtered, concentrated and purified by HPLC(Column:Chiralcel OD-3 150×4.6 mm I.D., 3 um); Condition: water(0.05%NH₃H₂O+10 mM NH₄HCO₃)-ACN; Gradient: from 64% to 94% of B; Flow rate: 30mL/min; Injections: 4; Column temperature: 35° C.) to afford 56 (50 mg,20.0%). The compound 56 (50 mg, 0.110 mmol) was purified by flash column(0˜20% of EtOAc in PE) to give 56 (7.8 mg, 15.6%). ¹H NMR (400 MHz,CDCl₃) δ_(H) 7.80 (s, 1H), 7.40 (s, 1H), 4.15-4.00 (m, 1H), 3.95-3.85(m, 1H), 3.45-3.30 (m, 6H), 2.56 (s, 1H), 2.00-1.90 (m, 1H), 1.85-1.65(m, 4H), 1.64-1.55 (m, 5H), 1.54-1.45 (m, 1H), 1.44-1.30 (m, 5H),1.29-1.15 (m, 4H), 1.14-1.00 (m, 4H), 0.98 (s, 3H), 0.93 (s, 3H), 0.82(s, 3H). LC-ELSD/MS purity 99%, MS ESI calcd. For C₂₈H₄₂N₃O [M−H₂O+H]⁺436.4 found 436.4.

EXAMPLE 57: Synthesis of1-((S)-2-cyano-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile(57)

Synthesis of 57.1

To a solution of 39.0 (3 g, 10.3 mmol) in toluene (50 mL) was addedacetic acid amine (2.38 g, 30.9 mmol), acetic acid (6.18 g, 103 mmol)and ethyl-1,2-isocyanoacetate (2.33 g, 20.6 mmol) at 25° C. under N₂.After stirring at 140° C. for 18 h the reaction mixture was quenchedwith saturated NH₄Cl aqueous (50 mL) at 20° C. The aqueous was extractedwith EtOAc (2×50 mL) and the combined organic phase were concentrated.The residue was purified by flash column (0˜20% of EtOAc in PE) to give57.1 (3.5 g). ¹H NMR (400 MHz, CDCl₃) δ_(H) 4.20-4.31 (m, 2H), 3.07-3.23(m, 1H), 2.68-3.02 (m, 2H), 1.72-1.92 (m, 5H), 1.38-1.69 (m, 11H),1.23-1.36 (m, 12H), 1.10-1.22 (m, 3H), 1.01 (s, 3H),

Synthesis of 57.2

To a solution of 57.1 (500 mg, 1.29 mmol) in EtOH (5 mL) was added NaBH₄(12.2 mg, 0.3225 mmol) at 0° C. under N₂. After stirring at 0° C. for0.5 h the reaction mixture was quenched with saturated aqueous NH₄Cl (10mL). The aqueous was extracted with EtOAc (2×10 mL) and the combinedorganic phase was concentrated. The residue was purified by flash column(0˜20% of EtOAc in PE) to give 57.2 (500 mg). ¹H NMR (400 MHz, CDCl₃)δ_(H) 4.09-4.29 (m, 2H), 3.23-3.42 (m, 1H), 1.98-2.24 (m, 2H), 1.63-1.89(m, 6H), 1.36-1.51 (m, 7H), 1.26 (m, 10H), 0.95-1.23 (m, 6H), 0.76 (d,J=4.4 Hz, 3H).

Synthesis of 57.3

To a solution of 57.2 (400 mg, 1.03 mmol) in acetone (10 mL), MeI (2.93mL, 46.3 mmol) and K₂CO₃ (1.44 g, 10.3 mmol) were added into thereaction mixture at 25° C. After stirring for 16 h at 25° C. the residuewas poured into water (20 mL). The aqueous phase was extracted withEtOAc (2×20 mL) and the combined organic phase was washed with water(2×20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated togive 57.3 (350 mg, 85%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 4.18-4.28 (m,2H), 1.76-2.01 (m, 8H), 1.63-1.72 (m, 3H), 1.46-1.51 (m, 2H), 1.35 (m,9H), 1.26 (m, 7H), 1.00-1.10 (m, 5H), 0.94 (s, 3H).

Synthesis of 57.4

To a solution of 57.3 (350 mg, 0.8715 mmol) in EtOH (10 mL) was addedNaBH₄ (491 mg, 13.0 mmol) at 25° C. under N₂. After stirring at 25° C.for 18 h the reaction mixture was quenched with saturated NH₄Cl aqueous(20 mL) at 25° C. The aqueous was extracted with EtOAc (2×20 mL) and thecombined organic phase was concentrated. The residue was purified byflash column (0-20% of EtOAc in PE) to give 57.4 (310 mg, 99%). ¹H NMR(400 MHz, CDCl₃) δ_(H) 3.91-3.99 (m, 1H), 3.51-3.60 (m, 1H), 1.58-1.98(m, 11H), 1.36-1.44 (m, 8H), 1.21-1.30 (m, 8H), 1.01-1.16 (m, 5H), 0.94(s, 3H).

Synthesis of 57.5

To a solution of 57.4 (310 mg, 0.8621 mmol) in DCM (20 mL) was addedN-Me-Im (87.2 mg, 0.8621 mmol), TEA (436 mg, 4.31 mmol) and TsCl (985mg, 5.17 mmol). After stirring at 20° C. for 2 h the mixture was washedwith water (40 mL), dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by column (0%-40% of EtOAc in PE) to give 57.5 (260mg, 58.8%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.79-7.85 (m, 2H), 7.36-7.40(m, 2H), 4.19-4.24 (m, 1H), 3.95-4.00 (m, 1H), 2.47 (s, 3H), 1.59-1.90(m, 10H), 1.54 (s, 3H), 1.33-1.50 (m, 12H), 0.98-1.15 (m, 6H), 0.84 (s,3H).

Synthesis of 57

To a solution of 57.5 (260 mg, 0.51 mmol) in DMF (5 mL) was added Cs₂CO₃(331 mg, 1.00 mmol), 4-cyano-pyrazole (94.0 mg, 1.01 mmol) and KI (83.9mg, 0.51 mmol) at 25° C. After stirring at 120° C. for 18 h the mixturewas washed with water (10 mL) and the aqueous phase was extracted withEtOAc (2×10 mL). The combined organic phase was washed with saturatedbrine (2×10 mL), dried over anhydrous Na₂SO₄, filtered, concentrated andpurified by flash column (60-80% of EtOAc in PE) to give 57 (130 mg,59%). 57 (110 mg, 0.2530 mmol, SFC spectra: SAGE-LXM−138-P1AK3) waspurified by SFC (Phenomenex-Cellulose-2 (250 mm*30 mm, 10 um)); Mobilephase: A: CO₂ B: 0.1% NH₃H₂O EtOH; gradient: from 55% to 55% of B,FlowRate(ml/min): 80) providing 57 (68.0 mg, 62%). ¹H NMR (400 MHz,CDCl₃) δ_(H) 8.10 (s, 1H), 7.83 (s, 1H), 4.66 (d, J=13.6 Hz, 1H), 4.16(d, J=14.0 Hz, 1H), 1.95-2.03 (m, 2H), 1.64-1.88 (m, 7H), 1.54 (s, 3H),1.44-1.45 (m, 1H), 1.38-1.52 (m, 5H), 1.24-1.32 (m, 7H), 1.18 (s, 3H),1.08-1.14 (m, 3H), 1.04 (s, 3H). LC-ELSD/MS 30-90AB_2 min_E, purity99%,; MS ESI calcd. for C₂₇H₃₈N₄O [M+H]⁺ 435.3, found 435.3.

EXAMPLES 58 & 59: Synthesis of1-((S)-2-hydroxy-2-((2R,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2-(methoxymethyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile(58) &1-((R)-2-hydroxy-2-((2R,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2-(methoxymethyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile(59) &1-((S)-2-hydroxy-2-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2-(methoxymethyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile(58A)&1-((R)-2-hydroxy-2-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2-(methoxymethyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile(59A)

Synthesis of 58.2

To a mixture of 58.1 (380 mg, 1.12 mmol) in DCM (10 mL) was added DMP(950 mg, 2.24 mmol) in portions. After stirring at 20° C. for 2 h, themixture was quenched with NaHCO₃ (30 mL) and Na₂S₂O₃ (30 mL) thenextracted with DCM (2×20 mL). The organic layer was washed with Na₂S₂O₃(2×100 mL, sat.), brine (300 mL, sat.), dried over Na₂SO₄, filtered andconcentrated to give 58.2 (600 mg). ¹H NMR (400 MHz, CDCl₃) δ_(H)3.70-3.66 (m, 1H), 3.42-3.23 (m, 4H), 2.47-2.40 (m, 1H), 2.18-1.60 (m,8H), 1.57-1.14 (m, 14H), 1.13-0.86 (m, 6H).

Synthesis of 58.3

To a suspension of Ph₃PEtBr (3.97 g, 10.7 mmol) in THE (20 mL) was addedt-BuOK (1.20 g, 10.7 mmol). After stirring at 40° C. for 30 min underN₂, 58.2 (600 mg, 1.79 mmol) in THE (20 mL) was added, then theresulting mixture was stirred at 40° C. for 16 h under N₂. The reactionmixture was poured into water (90 mL). The aqueous phase was extractedwith EtOAc (2×100 mL). The combined organic phase was washed with brine(100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. Theproduct was purified by flash column (0-10% EtOAc in PE) to give 58.3(350 mg). ¹H NMR (400 MHz, CDCl₃) δ_(H) 5.14-5.09 (m, 1H), 3.84-3.74 (m,1H), 3.42-3.29 (m, 5H), 2.38-2.13 (m, 3H), 1.96-1.51 (m, 7H), 1.49-1.03(m, 15H), 1.01-0.86 (m, 6H).

Synthesis of 58.4

To a solution of 58.3 (380 mg, 1.09 mmol) in THE (30 mL) was added 9-BBNdimer (797 mg, 3.27 mmol) at 25° C. under N₂. After stirring at 40° C.for 16 hours, the reaction mixture was cooled down and quenched withEtOH (0.8 mL, 13.0 mmol) at 0° C., followed by slow addition of NaOH(2.6 mL, 5M, 13.0 mmol). Then H₂O₂(1.63 mL, 16.3 mmol, 10 M in water)was added slowly maintaining the temperature below 30° C. The mixturewas stirred at 70° C. for another 1 h. The aqueous phase was extractedwith ethyl acetate (3×100 mL). The combine organic phase was washed withsaturated Na₂S₂O₃ (2×100 mL), brine (100 mL), drive over anhydrousNa₂SO₄, filtered and concentrated in vacuum to give a residue, which waspurified by flash column (0˜20% of EtOAc in PE) to give 58.4 (250 mg).¹H NMR (400 MHz, CDCl₃) δ_(H) 3.84-3.67 (m, 2H), 3.41-3.29 (m, 5H),1.95-1.59 (m, 8H), 1.53-1.18 (m, 13H), 1.16-0.75 (m, 9H), 0.66-0.65 (m,3H).

Synthesis of 58.5

To a solution of 58.4 (250 mg, 0.685 mmol) in DCM (10 mL) was added DMP(576 mg, 1.36 mmol) at 25° C. After stirring at 25° C. for 60 min, themixture was quenched with NaHCO₃ (300 mL) and Na₂S₂O₃ (300 mL) thenextracted with DCM (2×100 mL). The organic layer was washed with Na₂S₂O₃(2×100 mL, sat.), brine (300 mL, sat.), dried over Na₂SO₄, filtered andconcentrated in vacuum to give 58.5 (400 mg). ¹H NMR (400 MHz, CDCl₃)δ_(H) 3.78-3.71 (m, 1H), 3.45-3.32 (m, 5H), 2.56-2.50 (m, 2H), 2.26-1.85(m, 7H), 1.83-1.54 (m, 6H), 1.53-1.29 (m, 6H), 1.25-0.79 (m, 7H),0.63-0.60 (m, 4H).

Synthesis of 58.6

To a suspension of Ph₃PMeBr (1.57 g, 4.40 mmol) in THF (20 mL) was addedt-BuOK (493 mg, 4.40 mmol) at 25° C. under N₂. After stirring at 50° C.for 30 min, a solution of 58.5 (400 mg, 1.10 mmol) in THE (20 mL) wasadded dropwise to the resulting suspension, and then the mixture wasstirred at 50° C. for 2 h under N₂. The reaction mixture was poured into10% aq. NH₄Cl (100 mL). The aqueous phase was extracted with EtOAc(3×100 mL). The combined organic phase was washed with brine (100 mL),dried over anhydrous Na₂SO₄, filtered and concentrated. The product waspurified by flash column (0˜10% of EtOAc in PE) to give 58.6 (200 mg).¹H NMR (400 MHz, CDCl₃) δ_(H) 4.84 (s, 1H), 4.70 (s, 1H), 3.87-3.75 (m,1H), 3.42-3.31 (m, 5H), 2.04-1.56 (m, 9H), 1.51-1.18 (m, 12H), 1.15-0.83(m, 8H), 0.57 (s, 3H).

Synthesis of 58.7

To a solution of 58.6 (170 mg, 0.471 mmol) in DCM (10 mL) was addedm-CPBA (190 mg, 85%, 0.94 mmol) at 15° C. and stirred for 0.5 h. Themixture was quenched with saturated aq. NaHCO₃ (100 mL). The DCM phasewas separated and washed with saturated aq. NaHCO₃/Na₂S₂O₃ (1:1, 3×100mL), brine (100 mL), dried over Na₂SO₄, filtered and concentrated undervacuum to give 58.7 (250 mg). ¹H NMR (400 MHz, CDCl₃) δ_(H) 3.92-3.72(m, 1H), 3.42-3.30 (m, 5H), 2.88-2.87 (m, 0.7H), 2.56-2.49 (m, 1H),2.32-2.31 (m, 0.3H), 2.05-1.52 (m, 7H), 1.48-1.20 (m, 12H), 1.18-0.81(m, 10H), 0.79-0.67 (m, 3H).

Synthesis of 58 & 59 & 58A & 59A

To a solution of 58.7 (250 mg, 0.663 mmol) in DMF (10 mL) was added1H-pyrazole-4-carbonitrile (184 mg, 1.98 mmol) and Cs₂CO₃ (645 mg, 1.98mmol). After stirring at 130° C. for 16 hours, the reaction mixture wasdiluted with water (100 mL) and extracted with EtOAc (3×100 mL). Thecombined organic layer was washed with 5% LiCl (3×100 mL) andconcentrated. The residue was purified by flash column (0˜12% of EtOAcin PE) to give 200 mg of compound, which was purified by SFC (ColumnDAICEL CHIRALPAK IG (250 mm*30 mm, 10 um); Condition 0.1% NH₃H₂O ETOH;Begin B 60%; End B 60%) to give 58 (8.9 mg, 6%), 59 (10.1 mg, 6%), 58A(46.7 mg, 31%), 59A (22.2 mg, 14%).

58: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.92 (s, 1H), 7.81 (s, 1H), 4.36-4.33(m, 1H), 4.09-4.06 (m, 1H), 3.84 (s, 1H), 3.40-3.29 (m, 4H), 2.49 (s,1H), 2.02-1.56 (m, 8H), 1.49-1.12 (m, 12H), 1.11-0.91 (m, 13H).LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₇H₃₆N₃ [M−2H₂O-MeOH+H]⁺402.3found 402.3.

59: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.88 (s, 1H), 7.80 (s, 1H), 4.18-4.15(m, 1H), 4.02-3.99 (m, 1H), 3.85 (s, 1H), 3.40-3.29 (m, 6H), 2.32 (s,1H), 2.07-1.58 (m, 5H), 1.50-1.18 (m, 11H), 1.16-0.85 (m, 15H).LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₇H₃₆N₃ [M−2H₂O-MeOH+H]⁺402.3found 402.3.

58A: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.92 (s, 1H), 7.81 (s, 1H), 4.36-4.32(m, 1H), 4.10-4.07 (m, 1H), 3.71 (t, J=9.2 Hz, 1H), 3.41-3.34 (m, 4H),3.22 (s, 1H), 2.50 (s, 1H), 2.04-2.00 (m, 1H), 1.88-1.57 (m, 9H),1.46-1.14 (m, 10H), 1.11-0.85 (m, 12H). LC-ELSD/MS purity 99%, MS ESIcalcd. for C₂₇H₃₆N₃ [M−2H₂O-MeOH+H]⁺ 402.3 found 402.3.

59A: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.88 (s, 1H), 7.80 (s, 1H), 4.18-4.14(m, 1H), 4.02-3.99 (m, 1H), 3.71 (t, J=8.8 Hz, 1H), 3.41-3.34 (m, 4H),3.24 (s, 1H), 2.28 (s, 1H), 2.08-1.57 (m, 9H), 1.52-1.12 (m, 11H),1.09-0.88 (m, 12H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₇H₃₆N₃[M−2H₂O-MeOH+H]⁺ 402.3 found 402.3.

EXAMPLES 60 & 61: Synthesis of1-((S)-2-hydroxy-2-((2R,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2-methoxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile(60) &1-((R)-2-hydroxy-2-((2R,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2-methoxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile(61)

Synthesis of 60.1A & 60.1B

Compound 52.2 (16.0 g, 37.1 mmol) was added to collidine (150 mL, 37.1mmol) at 25° C. under N₂. The mixture was stirred at 140° C. for 16hours to give a solution. The mixture was poured into water (500 mL),extracted with EtOAc (3×400 mL). The combined organic phase was washedwith water (3×100 mL), brine (200 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under vacuum. The residue was purified byflash column (0-20% of EtOAc in PE) to give 60.1A and 60.1B (8.60 g). ¹HNMR (400 MHz, CDCl₃) δ_(H) 0.87 (s, 1H) 0.91 (s, 1H) 0.94-1.10 (m, 2H)1.10-1.33 (m, 6H) 1.53 (br dd, J=6.02, 2.76 Hz, 7H) 1.67-1.83 (m, 3H)1.83-1.97 (m, 3H) 2.28-2.72 (m, 3H) 5.31-5.55 (m, 1H) 5.60 (br s, 1H).

Synthesis of 60.2A & 60.2B

To a mixed solution 60.1A and 60.1B (8.60 g, 33.2 mmol) in DCM (90 mL)was added m-CPBA (10.0 g, 49.8 mmol) at 0° C. under N₂. After stirringat 25° C. for 2 h, the mixture was quenched with saturated NaHCO₃ (100mL) and extracted with DCM (2×150 mL). The organic layer was washed withNa₂S₂O₃ (2×100 mL, sat.), brine (2×100 mL), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuum. The residue was purified by flashcolumn (0˜20% of EtOAc in PE) to give 60.2A and 60.2B (4.60 g). ¹H NMR(400 MHz, CDCl₃) δ_(H) 30.64-0.82 (m, 1H) 0.71-0.89 (m, 1H) 0.82-0.86(m, 1H) 0.87 (br s, 1H) 0.9-1.12 (m, 2H) 1.12-1.33 (m, 4H) 1.30-1.44 (m,3H) 1.44-1.65 (m, 3H) 1.65-1.76 (m, 2H) 1.76-1.89 (m, 2H) 1.89-2.09 (m,3H) 2.09-2.74 (m, 2H) 2.76-3.31 (m, 1H).

Synthesis of 60.3A & 60.3B

To a solution of the mixture of 60.2A and 60.2B (4.80 g, 17.4 mmol) inMeOH (50 mL) was treated with 0.5 mL of H₂SO₄ (98%) at 25° C. for 3hours. The reaction mixture was treated with saturated NaHCO₃ (200 mL).The mixture was extracted with EtOAc (2×300 mL). The organic layer waswashed with brine (2×200 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The product was purified by flash column chromatography onsilica gel (0˜15% of EtOAc in PE) to give 60.3A and 60.3B (4.30 g). ¹HNMR (400 MHz, CDCl₃) δ_(H) 0.87 (s, 3H) 0.87-0.89 (m, 1H) 0.91-1.13 (m,3H) 1.14-1.35 (m, 6H) 1.35-1.60 (m, 4H) 1.70-2.01 (m, 4H) 2.06-2.65 (m,3H) 2.96-3.24 (m, 1H) 3.33 (s, 1H) 3.37 (s, 1H) 3.40 (s, 2H) 3.60-3.77(m, 1H).

Synthesis of 60.4A & 60.4B

To a solution of 60.3A and 60.3B (500 mg, 1.63 mmol) in DCM (10 mL) wasadded DMP (1.38 g, 3.26 mmol) at 25° C. under N₂. After stirring at 25°C. for 1 h, another batch of DMP (1.38 g, 3.26 mmol) was added to thereaction mixture at 25° C. under N₂. After stirring at 35° C. for 2 h,the mixture was quenched with saturated aqueous NaHCO₃ and saturatedaqueous Na₂S₂O₃ (50 mL, 1:1). The mixture was extracted with DCM (2×100mL). The combined organic phase was washed with a mixture of saturatedaqueous NaHCO₃ and saturated aqueous Na₂S₂O₃ (150 mL, 1:1), The combinedorganic phase was washed with brine (2×100 mL), dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was purified by pre-HPLC(Column:Welch Xtimate C18 150*25 mm*5 um; Condition: water (0.225%FA)-ACN; Begin B:70%; End B:100%) to afford 60.4A (50 mg, 10.0%) and60.4B (430 mg).

60.4A. ¹H NMR (400 MHz, CDCl₃) δ_(H) 5.70-5.65 (m, 1H), 5.42-5.36 (m,1H), 3.93-3.89 (m, 1H), 3.60-3.56 (m, 1H), 2.58-2.48 (m, 2H), 2.24-1.90(m, 6H), 1.80-1.10 (m, 16H), 1.00-0.87 (m, 1H), 0.60 (s, 3H). LC-ELSD/MSpurity 99%, MS ESI calcd. for C₁₉H₂₉O₃ [M+H]⁺ 305.2 found 305.2.

60.4B: ¹H NMR (400 MHz, CDCl₃) δ_(H) 0.70 (s, 1H) 0.83-0.91 (m, 3H)0.92-1.08 (m, 1H) 1.08-1.26 (m, 1H) 1.26-1.50 (m, 4H) 1.65-1.76 (m, 3H)1.76-1.90 (m, 2H) 1.90-2.02 (m, 2H) 2.05 (br d, J=8.78 Hz, 2H) 2.12-2.27(m, 1H) 2.27-2.36 (m, 1H) 2.45 (br dd, J=19.20, 8.66 Hz, 1H) 2.66-2.80(m, 1H) 3.01 (t, J=13.80 Hz, 1H) 3.25 (s, 1H) 3.26 (s, 1H) 3.27-3.28 (m,1H) 3.48 (br d, J=3.51 Hz, 1H).

Synthesis of 60.5

To a solution of 60.4A (350 mg, 1.14 mmol) in THE (10 mL) was addedMeMgBr (1.9 mL, 3 M in ethyl ether, 5.70 mmol) dropwise at −70° C. andthe mixture was stirred for 2 h. The reaction mixture was slowly pouredinto saturated aqueous citric acid (20 mL) at below 10° C. The aqueousphase was extracted with EtOAc (2×20 mL). The combined organic phase waswashed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to afford 60.5 (450 mg). ¹H NMR (400 MHz, CDCl₃) δ_(H) 3.37(s, 3H), 3.05 (s, 1H), 3.01 (br s, 1H), 2.43 (dd, J=8.2, 19.2 Hz, 1H),2.28-2.17 (m, 1H), 2.13-2.06 (m, 1H), 1.92-1.75 (m, 5H), 1.55-1.33 (m,8H), 1.22 (s, 3H), 1.21-1.03 (m, 5H), 0.87 (s, 3H).

Synthesis of 60.6

To a suspension of EtPh₃PBr (2.59 g, 7.00 mmol) in anhydrous THE (20 mL)was added t-BuOK (784 mg, 7.00 mmol) at 25° C. under N₂ and stirred at45° C. for 30 min. Then a solution of 60.5 (450 mg, 1.40 mmol) inanhydrous THE (10 mL) was added dropwise. The reaction mixture wasstirred for 16 h. The mixture was cooled and poured into water (25 mL)and stirred for 10 min. The aqueous phase was extracted with EtOAc (2×30mL). The combine organic phase was washed with brine (2×50 mL),filtered, dried over anhydrous Na₂SO₄, and concentrated. The residue waspurified by flash column (0˜15% of EtOAc in PE) to give 60.6 (350 mg,75.2%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 5.21-5.02 (m, 1H), 3.39 (s, 3H),3.09 (s, 1H), 3.00 (br s, 1H), 2.45-2.09 (m, 4H), 1.98-1.87 (m, 1H),1.86-1.77 (m, 2H), 1.70-1.57 (m, 6H), 1.54-1.31 (m, 6H), 1.22 (s, 3H),1.20-1.04 (m, 4H), 0.97-0.89 (m, 1H), 0.88 (s, 3H).

Synthesis of 60.7

To a solution of 60.6 (350 mg, 1.05 mmol) in THE (20 mL) was added 9-BBN(8.4 ml, 4.20 mmol, 0.5 M in THF) under N₂. The reaction mixture wasstirred at 50° C. under N₂ for 2 h. The mixture was cooled to 0° C. Thenethanol (0.902 mL, 15.7 mmol) and NaOH (3.13 mL, 5 M, 15.7 mmol) wereadded to the reaction mixture. Subsequently, H₂O₂(1.56 mL, 10 M, 15.7mmol) was added dropwise at 0° C. The mixture was stirred at 50° C. for2 hours. Saturated aqueous Na₂S₂O₃(50 mL) was added and the mixture wasstirred at 0° C. for another 1 hour. The reaction was checked withpotassium iodide-starch test paper to confirm excess H₂O₂ was destroyed.The aqueous phase was extracted with EtOAc (3×20 mL). The combinedorganic layer was washed with brine (2×50 mL), dried over anhydrousNa₂SO₄, filtered and concentrated to give 60.7 (350 mg).

Synthesis of 60.8

To a solution of 60.7 (350 mg, 0.998 mmol) in DCM (30 mL) was added DMP(1.69 g, 3.99 mmol) at 25° C. under N₂. After stirring at 25° C. for 0.5h, the resulting mixture was quenched with NaHCO₃ and Na₂S₂O₃ (50 mL,1:1). The mixture was extracted with DCM (2×50 mL). The combined organicphase was washed with a mixture of NaHCO₃ and Na₂S₂O₃ (50 mL, 1:1). Thecombined organic layer was washed with brine (2×30 mL), dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was purified byflash column (0-30% of EtOAc in PE) to give 60.8 (260 mg, 74.9%). ¹H NMR(400 MHz, CDCl₃) δ_(H) 3.40 (s, 3H), 3.07 (s, 1H), 3.02 (br s, 1H), 2.54(br t, J=8.7 Hz, 1H), 2.30-2.13 (m, 2H), 2.12 (s, 3H), 2.04-1.97 (m,1H), 1.92-1.77 (m, 3H), 1.68-1.59 (m, 3H), 1.51-1.26 (m, 7H), 1.22 (s,3H), 1.20-1.00 (m, 4H), 0.96-0.81 (m, 1H), 0.61 (s, 3H).

Synthesis of 60.9

To a suspension of MePh₃PBr (675 mg, 1.89 mmol) in anhydrous THE (15 mL)was added t-BuOK (212 mg, 1.89 mmol) at 15° C. under N₂ and stirred at60° C. for 30 min. Then a solution of 60.8 (220 mg, 0.63 mmol) inanhydrous THE (5 mL) was added dropwise. The reaction mixture wasstirred for 1 h. The mixture was cooled and poured into ice-water (50mL) stirred for 10 min. The aqueous phase was extracted with EtOAc (2×50mL). The combine organic phase was washed with brine (2×50 mL), filteredand concentrated. The residue was purified by flash column (0-10% ofEtOAc in PE) to give 60.9 (200 mg, 91.7%). ¹H NMR (400 MHz, CDCl₃) δ_(H)4.84 (s, 1H), 4.70 (s, 1H), 3.40 (s, 3H), 3.09 (s, 1H), 3.00 (br s, 1H),2.30-2.18 (m, 1H), 1.96-1.77 (m, 4H), 1.76 (s, 3H), 1.73-1.59 (m, 3H),1.53-1.31 (m, 6H), 1.22 (s, 3H), 1.20-1.00 (m, 5H), 0.91-0.78 (m, 3H),0.57 (s, 3H).

Synthesis of 60.10

To a solution of 60.9 (110 mg, 0.3174 mmol) in DCM (10 mL) was addedm-CPBA (128 mg, 0.64 mmol, 85%) and NaHCO₃ (53.3 mg, 0.64 mmol) at 0° C.under N₂. Then the mixture was stirred at 15° C. for 2 h. The mixturewas quenched with saturated NaHCO₃ (10 mL) and extracted with DCM (2×10mL). The organic layer was washed with Na₂S₂O₃ (2×10 mL, sat.), brine(2×10 mL), dried over anhydrous Na₂SO₄, filtered and concentrated togive 60.10 (100 mg).

Synthesis of 60 & 61

To a solution of 60.10 (100 mg, 0.28 mmol) in DMF (5 mL) was added1H-pyrazole-4-carbonitrile (51.3 mg, 0.55 mmol) and Cs₂CO₃ (179 mg, 0.55mmol) at 20° C. under N₂. After stirring at 130° C. for 16 hours, themixture was poured into H₂O (10 mL) and extracted with EtOAc (2×20 mL).The combined organic layer was washed with brine (20 mL), dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was purified byflash column (0-30% of EtOAc in PE), which was purified by SFC(Column:DAICEL CHIRALPAK AD(250 mm*30 mm, 10 um); Condition:0.1% NH₃H₂OIPA; Begin B:60%; End B:60%) to afford 60 (26.1 mg, Rt=2.091 min, 26.1%)and 61 (7.2 mg, Rt=2.275 min, 7.22%).

60: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.94 (d, J=2.5 Hz, 1H), 7.83 (d, J=2.5Hz, 1H), 4.42-4.02 (m, 2H), 3.39 (d, J=2.8 Hz, 3H), 3.11-2.95 (m, 2H),2.53 (d, J=2.8 Hz, 1H), 2.30-1.99 (m, 1H), 2.30-1.99 (m, 2H), 1.97-1.80(m, 2H), 1.70-1.32 (m, 9H), 1.23 (br s, 10H), 0.99 (d, J=2.5 Hz, 3H),0.93 (d, J=2.3 Hz, 4H). LC-ELSD/MS purity 99%, MS ESI calcd. forC₂₇H₃₈N₃O [M−2H₂O+H]⁺ 420.3 found 420.3.

61: ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.90 (s, 1H), 7.81 (s, 1H), 4.24-3.93(m, 2H), 3.39 (s, 3H), 3.14-2.94 (m, 2H), 2.29 (s, 4H), 1.95-1.60 (m,4H), 1.54-1.28 (m, 8H), 1.24-1.06 (m, 11H), 0.91-0.86 (m, 1H), 0.89 (s,4H). LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₇H₃₈N₃O [M−2H₂O+H]⁺420.3 found 420.3.

Steroid Inhibition of TBPS Binding

[³⁵S]-t-Butylbicyclophosphorothionate (TBPS) binding assays using ratbrain cortical membranes in the presence of 5 mM GABA has been described(Gee et al, J. Pharmacol. Exp. Ther. 1987, 241, 346-353; Hawkinson etal, Mol. Pharmacol. 1994, 46, 977-985; Lewin, A. H et al., Mol.Pharmacol. 1989, 35, 189-194).

Briefly, cortices are rapidly removed following decapitation of carbondioxide-anesthetized Sprague-Dawley rats (200-250 g). The cortices arehomogenized in 10 volumes of ice-cold 0.32 M sucrose using aglass/teflon homogenizer and centrifuged at 1500×g for 10 min at 4° C.The resultant supernatants are centrifuged at 10,000×g for 20 min at 4°C. to obtain the P2 pellets. The P2 pellets are resuspended in 200 mMNaCl/50 mM Na—K phosphate pH 7.4 buffer and centrifuged at 10,000×g for10 min at 4° C. This washing procedure is repeated twice and the pelletsare resuspended in 10 volumes of buffer. Aliquots (100 mL) of themembrane suspensions are incubated with 3 nM [³⁵S]-TBPS and 5 mLaliquots of test drug dissolved in dimethyl sulfoxide (DMSO) (final0.5%) in the presence of 5 mM GABA. The incubation is brought to a finalvolume of 1.0 mL with buffer. Nonspecific binding is determined in thepresence of 2 mM unlabeled TBPS and ranged from 15 to 25%. Following a90 min incubation at room temp, the assays are terminated by filtrationthrough glass fiber filters (Schleicher and Schuell No. 32) using a cellharvester (Brandel) and rinsed three times with ice-cold buffer. Filterbound radioactivity is measured by liquid scintillation spectrometry.Non-linear curve fitting of the overall data for each drug averaged foreach concentration is done using Prism (GraphPad). The data are fit to apartial instead of a full inhibition model if the sum of squares issignificantly lower by F-test. Similarly, the data are fit to a twocomponent instead of a one component inhibition model if the sum ofsquares is significantly lower by F-test. The concentration of testcompound producing 50% inhibition (IC₅₀) of specific binding and themaximal extent of inhibition (I_(max)) are determined for the individualexperiments with the same model used for the overall data and then themeans±SEM.s of the individual experiments are calculated. Picrotoxinserves as the positive control for these studies as it has beendemonstrated to robustly inhibit TBPS binding.

Various compounds are or can be screened to determine their potential asmodulators of [³⁵˜S]-TBPS binding in vitro. These assays are or can beperformed in accordance with the above

In Table 2 below, A indicates a TBPS IC₅₀ (μM)<0.1 μM, B indicates aTBPS IC₅₀ (μM) of 0.1 μM to <1.0 μM, C indicates a TBPS IC₅₀ (μM)of >1.0 μM.

TABLE 2 Compound No. Structure IC₅₀  1

A  2

A  3

A  4

A  5 A  6 A  7 A  8 B  9

B 10

C 11

A 12

B 13

B 14

C 15

A 16

A 17

B 18

19

A 20

B 21

A 22

A 23

B 24

A 25

B 26

A 27

B 28

A 29

A 30

B 31

A 32

B 33

B 34

A 35

B 36

B 37

B 38

A 39

A 40

A 41

A 42

A 43

A 44

A 45

B 46

A 47

A 48

A 49

A 50

A 51

A 52

A 53

B 54

B 55

B 56

A 57

A 58

A 59

B 58A

A 59A

B 60

A 61

B

Equivalents and Scope

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “of” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub-range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

1-104. (canceled)
 105. A method of treating a CNS-related disorder in asubject in need thereof, comprising administering to the subject atherapeutically effective amount of a compound of Formula (I-e6):

a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition comprising a compound of Formula (I-e6) or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient; wherein: each of R^(2a), R^(2b), R^(15a), andR^(15b) is hydrogen; R³ is unsubstituted C₁₋₃ alkyl, —CH₂OCH₃, or—CH₂OCH₂CH₃; R¹⁹ is hydrogen, methyl, or ethyl; R^(X) is —OH; R^(Y) ismethyl; and R²² is —CN.
 106. The method of claim 105, wherein R³ ismethyl, ethyl, or propyl.
 107. The method of claim 106, wherein R³ ismethyl.
 108. The method of claim 106, wherein R³ is ethyl.
 109. Themethod of claim 106, wherein R³ is propyl.
 110. The method of claim 105,wherein R³ is —CH₂OCH₃.
 111. The method of claim 105, wherein R³ is—CH₂OCH₂CH₃.
 112. The method of claim 105, wherein R¹⁹ is hydrogen. 113.The method of claim 105, wherein R¹⁹ is methyl.
 114. The method of claim105, wherein R¹⁹ is ethyl.
 115. The method of claim 105, wherein theCNS-related disorder is a sleep disorder, a mood disorder, aschizophrenia spectrum disorder, a convulsive disorder, a disorder ofmemory and/or cognition, a movement disorder, a personality disorder,autism spectrum disorder, pain, traumatic brain injury, a vasculardisease, a substance abuse disorder and/or withdrawal syndrome,tinnitus, or status epilepticus.
 116. The method of claim 105, whereinthe CNS-related disorder is depression.
 117. The method of claim 116,wherein the depression is postpartum depression.
 118. The method ofclaim 116, wherein the depression is major depressive disorder.
 119. Themethod of claim 118, wherein the major depressive disorder is moderatemajor depressive disorder.
 120. The method of claim 118, wherein themajor depressive disorder is severe major depressive disorder.
 121. Themethod of claim 105, wherein the CNS-related disorder is tremor. 122.The method of claim 121, wherein the tremor is essential tremor. 123.The method of claim 105, wherein the CNS-related disorder is seizure.124. The method of claim 105, wherein the CNS-related disorder isepilepsy or status epilepticus.
 125. The method of claim 124, whereinthe CNS-related disorder is status epilepticus, and wherein the statusepilepticus is convulsive status epilepticus or non-convulsive statusepilepticus.
 126. The method of claim 105, wherein the CNS-relateddisorder is Tourette's syndrome.
 127. The method of claim 105, whereinthe CNS-related disorder is obsessive compulsive disorder (OCD).
 128. Amethod of treating a CNS-related disorder in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a compound selected from Com- pound No. Structure 2

3

7

11

15

24

26

a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition comprising the compound or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable excipient.
 129. Themethod of claim 128, wherein the compound is a compound of the formula

or a pharmaceutically acceptable salt thereof.
 130. The method of claim128, wherein the compound is a compound of the formula

or a pharmaceutically acceptable salt thereof.
 131. The method of claim128, wherein the compound is a compound of the formula

or a pharmaceutically acceptable salt thereof.
 132. The method of claim128, wherein the compound is a compound of the formula

or a pharmaceutically acceptable salt thereof.
 133. The method of claim128, wherein the compound is a compound of the formula

or a pharmaceutically acceptable salt thereof.
 134. The method of claim128, wherein the compound is a compound of the formula

or a pharmaceutically acceptable salt thereof.
 135. The method of claim128, wherein the compound is a compound of the formula

or a pharmaceutically acceptable salt thereof.
 136. The method of claim128, wherein the CNS-related disorder is a sleep disorder, a mooddisorder, a schizophrenia spectrum disorder, a convulsive disorder, adisorder of memory and/or cognition, a movement disorder, a personalitydisorder, autism spectrum disorder, pain, traumatic brain injury, avascular disease, a substance abuse disorder and/or withdrawal syndrome,tinnitus, or status epilepticus.
 137. The method of claim 128, whereinthe CNS-related disorder is depression.
 138. The method of claim 137,wherein the depression is postpartum depression.
 139. The method ofclaim 137, wherein the depression is major depressive disorder.
 140. Themethod of claim 139, wherein the major depressive disorder is moderatemajor depressive disorder.
 141. The method of claim 139, wherein themajor depressive disorder is severe major depressive disorder.
 142. Themethod of claim 128, wherein the CNS-related disorder is tremor. 143.The method of claim 142, wherein the tremor is essential tremor. 144.The method of claim 128, wherein the CNS-related disorder is seizure.145. The method of claim 128, wherein the CNS-related disorder isepilepsy or status epilepticus.
 146. The method of claim 145, whereinthe CNS-related disorder is status epilepticus, and wherein the statusepilepticus is convulsive status epilepticus or non-convulsive statusepilepticus.
 147. The method of claim 128, wherein the CNS-relateddisorder is Tourette's syndrome.
 148. The method of claim 128, whereinthe CNS-related disorder is obsessive compulsive disorder (OCD).
 149. Amethod of treating a CNS-related disorder in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a compound selected from Com- pound No. Structure 29

42

44

a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition comprising the compound or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable excipient.
 150. Themethod of claim 149, wherein the compound is a compound of the formula

or a pharmaceutically acceptable salt thereof.
 151. The method of claim149, wherein the compound is a compound of the formula

or a pharmaceutically acceptable salt thereof.
 152. The method of claim149, wherein the compound is a compound of the formula

or a pharmaceutically acceptable salt thereof.
 153. The method of claim149, wherein the CNS-related disorder is a sleep disorder, a mooddisorder, a schizophrenia spectrum disorder, a convulsive disorder, adisorder of memory and/or cognition, a movement disorder, a personalitydisorder, autism spectrum disorder, pain, traumatic brain injury, avascular disease, a substance abuse disorder and/or withdrawal syndrome,tinnitus, or status epilepticus.
 154. The method of claim 149, whereinthe CNS-related disorder is depression.
 155. The method of claim 154,wherein the depression is postpartum depression.
 156. The method ofclaim 154, wherein the depression is major depressive disorder.
 157. Themethod of claim 156, wherein the major depressive disorder is moderatemajor depressive disorder.
 158. The method of claim 156, wherein themajor depressive disorder is severe major depressive disorder.
 159. Themethod of claim 149, wherein the CNS-related disorder is tremor. 160.The method of claim 159, wherein the tremor is essential tremor. 161.The method of claim 149, wherein the CNS-related disorder is seizure.162. The method of claim 149, wherein the CNS-related disorder isepilepsy or status epilepticus.
 163. The method of claim 162, whereinthe CNS-related disorder is status epilepticus, and wherein the statusepilepticus is convulsive status epilepticus or non-convulsive statusepilepticus.
 164. The method of claim 149, wherein the CNS-relateddisorder is Tourette's syndrome.
 165. The method of claim 149, whereinthe CNS-related disorder is obsessive compulsive disorder (OCD).